1

 

                DEPARTMENT OF HEALTH AND HUMAN SERVICES

 

                      FOOD AND DRUG ADMINISTRATION

 

                CENTER FOR DRUG EVALUATION AND RESEARCH

 

 

 

 

 

 

 

 

 

 

 

 

 

               PULMONARY-ALLERGY DRUGS ADVISORY COMMITTEE

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

                        Thursday, June 10, 2004

 

                               8:03 a.m.

 

 

 

 

 

 

 

                        Holiday Inn Gaithersburg

                              The Ballroom

                     Two Montgomery Village Avenue

                         Gaithersburg, Maryland

                                                                 2

                              PARTICIPANTS

 

      Vernon Chinchilli, Ph.D., Acting Chair

      Shalini Jain, PA-C, MBA, Executive Secretary

 

      MEMBERS

 

                Carolyn M. Kercsmar, M.D.

                Fernando D. Martinez, M.D.

                Theodore F. Reiss, M.D. (Industry Rep)

                Michael Schatz M.D., M.S.

                Karen S. Schell, RRT, (Consumer Rep)

                Erik R. Swenson, M.D.

 

      SPECIAL GOVERNMENT EMPLOYEE CONSULTANTS (VOTING)

 

                T. Prescott Atkinson, M.D., Ph.D.

                I. Marc Moss, M.D.

                Wayne Mitchell, M.D.

                                                                 3

 

                            C O N T E N T S

 

                                                              PAGE

 

      Call to Order and Opening Remarks:

                Vernon Chinchilli, Ph.D.                         5

 

      Introductions                                              6

 

      Conflict of Interest Statement:

                Shalini Jain, PA-C, MBA                          7

 

      Opening Remarks:

                Robert Meyer, M.D.                              10

 

      History of the Montreal Protocol and 21 CFR 2.125         13

 

      Medical Considerations:

                Eugene Sullivan, M.D.                           40

 

      Economic Considerations:

                Randall Lutter, Ph.D.                           60

 

      Questions from the Committee to the Speakers              76

 

      Open Public Hearing (1)

                Pamela Wexler, U.S. Stakeholders Group          93

                Elaine Jones, Ph.D. GlaxoSmithKline            104

                Ron Garutti, M.D., Schering-Plough             119

 

      Open Public Hearing (2)

                Ballard Jamieson, Jr., International           143

                  Pharmaceutical Aerosol Consortium

                Neil Flanzraich, IVAX Corporation              149

                Richard Rozek, Ph.D., National Economic        162

                  Research Associates

                David Doniger, Natural Resources               172

                  Defense Council

                Joseph Rau, M.D., American Association         181

                  for Respiratory Care

                Jodi Finder, Asthma Therapy Coalition          183

                Steven Bernhardt, M.D.,                        190

                  Honeywell Chemicals

                                                                 4

 

                      C O N T E N T S (Continued)

 

      Open Public Hearing (2) (Continued)

                Nancy Sander, Allergy and Asthma Network       193

                  Mothers of Asthmatics

                Anthony Marinelli, M.D., American              198

                  Thoracic Society

                Ira Finegold, M.D., College of Allergy,        203

                  Asthma and Immunology

                Spenser Atwater, M.D., Joint Council on        207

                  Allergy, Asthma and Immunology

                 (statement read by Ms. Jain)

 

      Committee Discussion                                     211

 

      Adjournement                                             282

 

                                                                 5

 

                         P R O C E E D I N G S

 

                   Call to Order and Opening Remarks

 

                DR. CHINCHILLI:  Good morning, everyone.

 

      This is a meeting of the Pulmonary-Allergy Drugs

 

      Advisory Committee.  We are here today to discuss

 

      whether the use of chorofluorocarbons as

 

      propellants in albuterol-metered dose inhalers in

 

      no longer an essential use under the criteria as

 

      set forth in the Code of Federal Regulations 12 CFR

 

      1.125.

 

                My name is Vern Chinchilli.  I am the

 

      Acting Chair today for the committee.  So we will

 

      have some opening remarks.  The first thing I

 

      usually do is introduce--I will ask each committee

 

      member--we will go around the table--to introduce

 

      themselves.  Please make sure you hit the

 

      microphone button so it is on.

 

                Why don't we start with Dr. Reiss.  Oh; he

 

      is not here?  Dr. Atkinson?

 

                DR. ATKINSON:  I am Prescott Atkinson,

 

      Allergy and Immunology at University of Alabama in

 

      Birmingham.

 

                                                                 6

 

                DR. SCHELL:  Karen Schell, Consumer

 

      Representative from Kansas.

 

                DR. MARTINEZ:  I am Fernando Martinez from

 

      the Arizona Respiratory Center, University of

 

      Arizona.

 

                DR. SCHATZ:  I am Michael Schatz, Allergy

 

      and Immunology, Kaiser Permanent, San Diego.

 

                DR. KERCSMAR:  Carolyn Kercsmar, pediatric

 

      pulmonology, Rainbow Babies and Children's Hospital

 

      in Cleveland.

 

                DR. MOSS:  Mark Moss, Pulmonary and

 

      Critical Care, Emory University in Atlanta,

 

      Georgia.

 

                DR. CHINCHILLI:  Vern Chinchilli.  I am a

 

      biostatistician from the Penn State Hershey Medical

 

      Center.

 

                MS. JAIN:  Shalini Jain, Exec Sec, Acting,

 

      and, at this point, for this meeting for the

 

      Pulmonary-Allergy Drugs Advisory Committee.

 

                DR. SWENSON:  Erik Swenson, Pulmonary and

 

      Critical Care Medicine at the University of

 

      Washington in Seattle.

 

                                                                 7

 

                DR. LUTTER:  Randy Lutter, Economics, with

 

      the Office of the Commissioner in FDA.

 

                DR. MITCHELL:  Wayne Mitchell, Office of

 

      Regulatory Policy in the Center for Drug Evaluation

 

      and Research.  I am the draftsman on the rule.

 

                DR. SULLIVAN:  I am Gene Sullivan.  I am

 

      the Deputy Director of the Division of Pulmonary

 

      and Allergy Drug Products at FDA.

 

                DR. MEYER:  I am Bob Meyer.  I am the

 

      Director of the Office of Drug Evaluation II in the

 

      Center for Drugs at FDA.

 

                DR. CHINCHILLI:  Thank you, everyone, for

 

      attending.

 

                Next, Shalini Jain will talk about the

 

      Conflict of Interest Statement.

 

                     Conflict of Interest Statement

 

                MS. JAIN:  The following statement

 

      addresses the issue of conflict of interest with

 

      respect to this meeting and is made part of the

 

      record to preclude even the appearance of such at

 

      this meeting.

 

                Based on the agenda, it has been

 

                                                                 8

 

      determined that the topics of today's meeting are

 

      issues of broad applicability and there are no

 

      products being approved at this meeting.  Unlike

 

      issues before a committee in which a particular

 

      product is discussed, issues of broader

 

      applicability involve many industrial sponsors and

 

      academic institutions.  All special government

 

      employees have been screened for their financial

 

      interests as they may apply to the general topic at

 

      hand.

 

                Because there has been reported interest

 

      in pharmaceutical companies, the Food and Drug

 

      Administration has granted general-matters waivers

 

      to the special government employees who require a

 

      waiver under Title 18, United States Code Section

 

      208 which permits them to participate in today's

 

      discussion.

 

                A copy of the waiver statement may be

 

      obtained by submitting a written request to the

 

      agency's Freedom of Information Office, Room 12A-30

 

      of the Parklawn Building.  Because general topics

 

      impact so many entities, it is not prudent to

 

                                                                 9

 

      recite all potential conflicts of interest as they

 

      apply to each member, consultant and guest speaker.

 

                FDA acknowledges that there may be

 

      potential conflicts of interest but, because of the

 

      general nature of the discussion before the

 

      committee, the potential conflicts are mitigated.

 

      With respect to FDA's invited industry

 

      representative, we would like to disclose that Dr.

 

      Theodore Reiss is participating in this meeting as

 

      an industry representative acting on behalf of

 

      regulated industry.  Dr. Reiss is employed by

 

      Merck.

 

                In the event that the discussion involves

 

      any other products or firms not already on the

 

      agenda for which an FDA participant has a financial

 

      interest, the participants are aware of the need to

 

      exclude themselves from such involvement and their

 

      exclusion will be noted for the record.

 

                With respect to all other participants, we

 

      ask, in the interest of fairness, that they address

 

      any current or previous financial involvement with

 

      any firm whose products they may wish to comment

 

                                                                10

 

      upon.

 

                Thank you.

 

                DR. CHINCHILLI:  Thank you, Ms. Jain.

 

                We are ready to start the regular part of

 

      the agenda.  Dr. Meyer, the Director of the Office

 

      of Drug Evaluation II, will have some opening

 

      remarks.

 

                            Opening Remarks

 

                DR. MEYER:  Good morning.  Although I

 

      service Director of the Office of Drug Evaluation

 

      II in the Center for Drugs, I, for many years,

 

      served for the Center Lead on issues related to the

 

      Montreal protocol and phase-out of CFCs from

 

      FDA-regulated medical products, specifically MDIs

 

      for asthma and COPD.

 

                So, on behalf of the FDA, I wish to

 

      welcome all the participants in today's meeting of

 

      the Pulmonary and Allergy Drugs Advisory Committee.

 

      I want to thank you in advance for your time and

 

      your efforts and your thoughtfulness in your

 

      discussions and advice.

 

                When we were originally planning this

 

                                                                11

 

      meeting, we had hoped the meeting would coincide

 

      with the open public comment period of a proposed

 

      rule to delist albuterol as an essential use of

 

      ozone-depleting substances, specifically CFCs.

 

      This is now, indeed, the case although the rule

 

      just went on display at the Federal Register and,

 

      subsequently, on our web page yesterday afternoon.

 

      I believe you have been provided copies.

 

                I would point out that, although the

 

      proposed rule  is posted on these sites, it is not

 

      officially published until June 16 so what you have

 

      in hand is a pre-publication version that means

 

      some dates are missing and the pagination will

 

      change when it is officially published in the

 

      Federal Register.

 

                I would also point out that the six-day

 

      comment period starts on the day of official

 

      publication which will be June 16 although,

 

      clearly, the discussions today will be considered

 

      as part of the docket for us to consider in coming

 

      to the final rule.

 

                We particularly look foreword today to

 

                                                                12

 

      input from the public in our public hearing portion

 

      of the meeting and I thank those individuals and

 

      organizations who are presenting or have otherwise

 

      submitted materials for the record.

 

                All of the presentations, submissions and

 

      the deliberations of the committee and advice given

 

      today will be entered into the docket, as I said,

 

      and will help us to move forward towards finalizing

 

      this rule with a target of Summer of 2005.

 

                I would note to the committee that we are

 

      not seeking any formal votes today on a particular

 

      question but do, very much, seek your counsel on

 

      the matter at hand whether the use of CFCs in

 

      albuterol metered-dose inhalers remains an

 

      essential use under the provisions of our

 

      regulations.

 

                We will have three speakers from the FDA

 

      today.  I will first speak, giving a history of the

 

      Montreal Protocol and FDA's regulations regarding

 

      essential use of CFCs.  Dr. Eugene Sullivan, from

 

      the Division of Pulmonary and Allergy Drug

 

      Products, will then follow with considerations

 

                                                                13

 

      related to the current situation with albuterol and

 

      its essentiality as well as some related issues.

 

                To close FDA's presentations, Randy

 

      Lutter, who is FDA's Chief Economist in the Office

 

      of Planning, will speak on economic considerations

 

      related to the potential for delisting albuterol as

 

      an essential use.

 

                Again, we would like to thank you for your

 

      time in being here and look forward to today's

 

      discussion.

 

                DR. CHINCHILLI:  Thank you, Dr. Meyer.

 

                I believe you are on the agenda next for

 

      your presentation.

 

           History of the Montreal Protocol and 21 CFR 1.125

 

                DR. MEYER:  Good morning, again, from this

 

      venue.  When I arrived at the agency about ten

 

      years ago this July, I can assure you that I never

 

      envisioned I would be standing here representing

 

      the FDA on the issue of ozone protections.  As a

 

      pulmonologist, it was not something that entered my

 

      mind at that point.

 

                But life is full of happy occurrences. 

 

                                                                14

 

      This picture on my title slide is from NASA's web

 

      page and shows the largest recorded ozone hole over

 

      the Antarctic which actually was shot last

 

      September of 2003.  This serves as a fitting

 

      graphic to start a talk on the history of the

 

      Montreal Protocol as well as the FDA regulations

 

      that related to chlorofluorocarbons and

 

      ozone-depleting substances.

 

                The stratosphere is a region of the

 

      earth's atmosphere that begins roughly ten to

 

      fifteen kilometers above the earth's surface,

 

      depending on the particular part of the earth one

 

      is focused on, and extends up to 50 kilometers.

 

      Most of the ozone, over 90 percent of the ozone, in

 

      the atmosphere is in this stratosphere where it

 

      acts, in part, to filter ultraviolet B radiation by

 

      absorbing this band of wave length from sunlight.

 

                Increases in UV-B reaching the earth's

 

      surface are detrimental to human health in a number

 

      of ways as well as to other life forms and to

 

      synthetic materials.  The human consequences of

 

      most note are increases in skin cancer as well as

 

                                                                15

 

      cataracts and alterations in immunity.  Those skin

 

      cancers are both of the melanoma type as well as

 

      non-melanoma.

 

                This, then, is the background as to why

 

      there is a worry about protecting the ozone layer.

 

      Also, by way of background, since we are talking

 

      about regulations, I would like to explain how

 

      rules are made.  The FDA operates under laws or

 

      statutes, most notably the Food, Drug and Cosmetic

 

      Act, as well as other statutes.

 

                However, no matter how well written or

 

      detailed a law may be, it cannot provide sufficient

 

      detail to inform the specific process of

 

      regulation.  This is accomplished by the writing of

 

      rules which, when finalized, have the force of law

 

      behind them as it represents the agency's

 

      implementation of the respective law that we are

 

      operating under.

 

                The usual pathway for reaching a final

 

      regulation or rule is by what is called Notice and

 

      Comment Rulemaking.  Formally, that involves the

 

      FDA publishing a Notice of Proposed Rulemaking, or

 

                                                                16

 

      NPR, in the Federal Register such as will shortly

 

      occur for albuterol.

 

                An NPR typically has a comment period

 

      between 60 and 90 days--again, that, for the rule

 

      at hand is 60 days beginning on June 16--during

 

      which time comments from the public, including the

 

      regulated industry, are solicited.  These comments

 

      are then individually considered and addressed in

 

      reaching a final rule.  Rulemaking is an integral

 

      part of the CFC non-essentiality determinations.  I

 

      will speak more on this later.

 

                The purpose of my talk, then, this

 

      morning, is to give a history and background of the

 

      Montreal Protocol and to FDA's regulations with

 

      regard to ozone protection.  The timeframes for

 

      these, as they developed, overlap and, obviously,

 

      the efforts intersect.  So I will interweave the

 

      two topics in my talk.

 

                Back in the mid-1970s, two scientists

 

      operating out of trial University of California at

 

      Irvine posited that chlorofluorocarbons were

 

      reaching the stratosphere were UV radiation slowly

 

                                                                17

 

      would cleave off the chloride atoms that, in turn,

 

      catalyze the destruction of ozone.  This work was

 

      by Molina and Rowland, who later was awarded the

 

      Nobel Prize.

 

                At the time that this article came out,

 

      chlorofluorocarbons, or CFCs, were ubiquitous in

 

      use in multiple applications.  They became

 

      widespread for a number of reasons.  Amongst these

 

      were that CFCs are quite non-toxic which,

 

      parenthetically, makes them excellent for use in

 

      inhalers, very stable and had physical-chemical

 

      properties that were advantageous for use in

 

      refrigerant systems, air conditioners and aerosols.

 

                The stability of these gasses is, in part,

 

      why they are so devastating to the stratosphere.

 

      They have a very long half-life when they reach the

 

      stratosphere and, therefore, damage the ozone layer

 

      for many, many years.

 

                In 1978, really in a fairly remarkably

 

      short time after the seminal publication by Rowland

 

      and Molina, the U.S. Government acted to address

 

      the issue of CFCs and to place a general ban on the

 

                                                                18

 

      use of CFCs as propellants in consumer aerosol

 

      products.  This was accompanied by a rule from FDA

 

      in the relevant chapter of the Code of Federal

 

      Regulations or what we call the CFR, and that, for

 

      the FDA, is the 21st Chapter, banning the use of

 

      CFCs in all regulate products except for those

 

      deemed as essential uses.

 

                This rule is now called 2.125 because that

 

      is the citation where it is published.  That is how

 

      we will be referring to it throughout much of the

 

      day.  Notably exempt  at that time were broad

 

      classes of asthma and allergy products such as a

 

      nasal steroids, the inhaled steroids, and

 

      adrenergic bronchodilators.

 

                In 1987, as the science of ozone depletion

 

      advanced and as there was further evidence

 

      accumulated about ozone reductions, a global treaty

 

      known as the Montreal Protocol on substances that

 

      deplete the ozone layer was initiated.  At that

 

      time, 27 nations, including the USA, were

 

      signatories.

 

                I would note, just to make this topical to

 

                                                                19

 

      sort of current events, that this was during the

 

      latter years of the Reagan Administration.  The

 

      original protocol now has at least 184 signatory

 

      countries.  As of the time that I queried the web

 

      page for the Secretariat of the Ozone Efforts about

 

      a month, it was 184 countries.  Countries are also

 

      called parties under the terms of the protocol.

 

                This is widely considered a successful

 

      example of global, environmental cooperation.

 

      Indeed, there is evidence that the chloride levels

 

      in the stratosphere have stabilized in recent years

 

      and it is expected that the stratospheric ozone

 

      layer will slowly recover to levels that were seen

 

      in the early 1980s by the middle part of this

 

      current century.

 

                The original phase-out of CFCs was slated

 

      for the Year 2000.  That was taken in London in

 

      1990.  This was moved up, however, by meeting of

 

      the parties in Copenhagen which occurred in 1992.

 

      It was moved up to 1995, at the end of '95, because

 

      of increasing evidence of marked ozone depletion,

 

      particularly over the extreme southern hemisphere,

 

                                                                20

 

      as you saw in my first slide.

 

                This phenomenon is commonly called an

 

      ozone hole.  It is not really a true hole but an

 

      area of extreme depletion.  I should point out

 

      that, although it is a depletion that is

 

      particularly prominent over the southern

 

      hemisphere, it has occurred globally.

 

                I should also point out that, while we are

 

      focussing on CFCs today because that is the

 

      relevant topic for the FDA, the protocol, itself,

 

      has controls on many other ozone-depleting

 

      substances such as halons, HCFCs, methylbromide,

 

      carbon tetrachloride and other substances.

 

                So, while the CFCs are an important issue

 

      to FDA and, indeed, to the Montreal Protocol, I do

 

      want to be clear that the protocol is a much

 

      broader effort in scope than simply the

 

      chlorofluorocarbons.

 

                In accordance with the Copenhagen

 

      Amendment to the protocol, the production and

 

      importation of CFCs became illegal in economically

 

      developed countries including the United States as

 

                                                                21

 

      of January 1, 1996.  The rest of the world is

 

      expected to have phased out new CFCs by 2010.

 

      Metered-dose inhalers, or MDIs, for asthma and COPD

 

      are currently considered as potentially acceptable

 

      essential uses of CFCs.  I say potentially

 

      acceptable because there is a nomination process

 

      that parties undergo if they want to produce or

 

      import CFCs for use in MDIs.

 

                These nominations have to be done annually

 

      and the process generally begins nearly two years

 

      prior to the year in question.  So, for instance,

 

      the U.S. had to submit its nomination for 2006 in

 

      early 2004.

 

                I would also point out that nominations

 

      are historically approved by consensus of the

 

      parties to the Montreal Protocol but, actually, if

 

      the consensus process fails, there is a mechanism

 

      within the protocol to default to a two-thirds

 

      majority decision.

 

                I wanted to go through sort of how the

 

      protocol has evolved over time  This is a decision

 

      of the parties from the Copenhagen meeting. 

 

                                                                22

 

      Decision IV, or this IV, means that it was from the

 

      fourth meeting of the parties and it was the 25th

 

      decision taken at that meeting.  This was the

 

      definition at the time that they decided the

 

      phase-out would begin on January 1, 1996, or the

 

      ban on CFCs, that stated that, "All essential uses

 

      of CFCs would have to be based on products being

 

      necessary for public health and that there were not

 

      adequate alternatives."  The failure to have

 

      adequate alternatives could either be based on

 

      technical problems or economical problems.

 

                But this was macroscopic in terms of both

 

      this determination as well as the general use.  In

 

      other words, it was widely accepted at that point

 

      in general that the uses of CFCs and MDIs for

 

      asthma and COPD could be considered an essential

 

      use.

 

                However, over time, the protocol evolved

 

      so that, as the phase-out progressed, as

 

      alternatives became available, this sort of more

 

      generally and broad interpretation of what was an

 

      essential use became narrower and narrower in

 

                                                                23

 

      scope.

 

                In Beijing, at the twelve meeting of the

 

      parties in the Year 2000, another decision was

 

      taken that said that any product approved after

 

      December, 2000, must individually meet these

 

      criteria for essentiality under Decision IV-25.

 

      So, in other words, it is not just a general

 

      consensus any longer that the use of CFCs for

 

      asthma and COPD was acceptable but, in this case,

 

      any new product would have to individually meet

 

      this.

 

                So this was a product-centered

 

      determination of essentiality that essentially

 

      precluded new CFC generics and, actually, many

 

      other new CFC products.  It essentially was

 

      shutting the door, for all intents and purposes,

 

      except under extraordinary circumstances for any

 

      new CFC MDIs.

 

                This past year, in Nairobi, a further

 

      decision was taken by the parties that became even

 

      more narrow and specific in scope.  It stated that

 

      essential-use nominations from parties which, in

 

                                                                24

 

      the past, had been lumped and general and not

 

      parsed out for the purposes of the protocol's

 

      evaluation, or the Montreal Protocol evaluation.

 

                Now it stated that essential-use

 

      nominations have to be specific; for example, a

 

      country might say they need some

 

      undetermined--well, they would have to give a

 

      specific number, but some number of tons for

 

      albuterol.  No quantity of essential-use CFCs would

 

      be authorized for albuterol.  This is, I think,

 

      particularly germane today--that no quantity of

 

      essential uses of CFCs would be authorized,

 

      period--actually, this is a little bit of a

 

      misstatement in the way this is terms--if a country

 

      does not submit to the meetings of the

 

      party--beginning of the open-ended working group,

 

      excuse me, in the summer of 2005--a clear plan for

 

      when albuterol, specifically, would no longer be

 

      essential.

 

                Let me go through that again, because this

 

      is key.  Countries who request essential uses,

 

      including the United States, will have to submit to

 

                                                                25

 

      the Ozone Secretariat of the Open-Ended Working

 

      Group in the summer of 2005 a plan or a

 

      date-certain for when albuterol will no longer be

 

      considered essential. If parties fail to do that,

 

      including the U.S., we will not receive and

 

      essential-use allocation at all.

 

                Now, turning a little bit from the

 

      evolution of the Montreal Protocol back to our

 

      rules and regulations, the Clean Air Act Amendments

 

      of 1990 codified the Montreal Protocol into U.S.

 

      law.  The implementing EPA regulations specifically

 

      call for FDA to define what is an essential medical

 

      use and refers to our 2.125 as the source of the

 

      listing of those essential products.

 

                I remind you, however, that 1.125 was

 

      finalized before the Montreal Protocol existed and

 

      before the Clean Air Act Amendments.

 

                The rule, as promulgated in 1978, stated

 

      that a  CFC-containing product regulated by FDA was

 

      misbranded or adulterated under the FD&C Act; that

 

      is, it would be illegal under our authority unless

 

      deemed essential and listed in 2.125.  The

 

                                                                26

 

      definition of essential was that there would be no

 

      technically feasible alternatives; that the use of

 

      CFCs in that particular product provided

 

      substantial health, public or environmental

 

      benefit; and that the release of the CFC was small

 

      or justified given the public-health benefit.

 

                Notably, the FDA rule had no mechanism to

 

      determine when things were no longer essential and,

 

      therefore, to delist them.  It did have ways to add

 

      new classes of drugs to the list and, in fact, that

 

      was done over the years.  But it had no specified

 

      way for delisting things.

 

                Another important feature of the rule that

 

      needed to be correct is that many drugs, including

 

      albuterol, were not specifically mentioned as

 

      essential uses but, rather, there were broad

 

      definitions of drug classes, if you will, such as

 

      albuterol and other beta-agonists being under the

 

      general term of adrenergic bronchodilators for

 

      human use.

 

                So, realizing that we needed to correct

 

      some things about this rule that was written prior

 

                                                                27

 

      to the Montreal Protocol and the Clean Air Act, and

 

      specifically to develop a mechanism for delisting

 

      things that were no longer essential, FDA, in 1996,

 

      undertook revisions.  Because of wanting to do

 

      these revisions in the very most public and

 

      informed manner, the FDA took an additional step to

 

      the steps that I gave you earlier for the

 

      publication of a rule, doing something called an

 

      Advance Notice of Proposed Rulemaking which,

 

      actually, starts with another cycle of notice and

 

      comment.

 

                This effort proved very successful if

 

      measured by the number of comments.  We got close

 

      to 10,000 comments to this Advance Notice of

 

      Proposed Rulemaking, many of which, I would point

 

      out, were actually patient-based comments sparked

 

      by lobbying efforts.

 

                We then took all 10,000 comments and

 

      reviewed them and responded to them.  I would note

 

      that there were many fewer substantive comments but

 

      still all of the comments were carefully reviewed

 

      and considered.  That resulted in the publication

 

                                                                28

 

      of a Notice of Proposed Rulemaking in 1999.

 

                That proved to be less controversial in

 

      many ways and it received many fewer substantive

 

      comments and comments overall and, as I said, had

 

      seemingly much less controversy.  So FDA moved

 

      forward with amending 2.125 in July of 2002 and

 

      this went into effect six months later.

 

                The 2002 revisions did a number of things.

 

      First of all, it listed essential uses as

 

      individual moieties.  I would point out that, to

 

      coincide more correctly with the Montreal Protocol,

 

      it no longer referred simply to chlorofluorocarbons

 

      but to ozone-depleting substances.  But, for the

 

      purposes of today and for all intents and purposes,

 

      most of FDA's activities, you can consider ODS, or

 

      ozone-depleting substances, as being synonymous

 

      with CFCs in terms of this discussion.

 

                So, for instance, albuterol is now

 

      separately listed rather than there just being a

 

      broad class without any citation of individual

 

      moieties.

 

                The revisions also added a higher hurdle

 

                                                                29

 

      for investigational new drugs to be developed with

 

      CFCs and it raised the bar for new listings of

 

      essential uses as well.  There was also a list of

 

      criteria, importantly for today, for determining

 

      when individual uses were no longer considered

 

      essential.

 

                One other revision I would point out that

 

      is not on this slide was that we shifted the rule,

 

      because of the re-write of the Clean Air Act, to

 

      state that if something was no longer essential, it

 

      would be considered illegal to market it under the

 

      Clean Air Act and not under the Food, Drug and

 

      Cosmetic Act.

 

                Let me go through these important

 

      nonessentiality criteria.  I would point out that

 

      Dr. Sullivan will revisit these in his talk

 

      specific to albuterol, but I think they are worth

 

      hearing a couple of times.

 

                For a specific moiety to be considered

 

      nonessential, there would have to be at least one

 

      non-ozone-depleting-substance product--in other

 

      words, a non-CFC product--with that same active

 

                                                                30

 

      moiety, and here I am only talking about a moiety

 

      where there is only one marketed-brand product or

 

      one marketing strength, so, at least one active

 

      moiety with the same indications, same route of

 

      administration--in other words, oral albuterol

 

      would not be considered an alternative under these

 

      criteria--and about the same level of convenience.

 

                We stated in the preamble to the final

 

      rule that, although dry-powdered inhalers might fit

 

      this description, we felt that MDIs would most

 

      neatly do so and, I think, most logically do so.

 

                In addition to this, these alternatives

 

      would have to have adequate postmarketing data to

 

      prove that they are not only safe and effective for

 

      approval purposes but will serve as an adequate

 

      alternative in the marketplace.  Importantly, there

 

      would have to be production capabilities and

 

      supplies that are adequate to meet the needs of

 

      patients who depend on the use of this moiety for

 

      the treatment of their asthma or COPD and patients

 

      who require the CFC product are adequately served.

 

                I would state, and I am sure that Gene

 

                                                                31

 

      will bring this up as well, that, under the

 

      considerations for adequately served, is the issue

 

      of price in that--not so much whether there will be

 

      any impact on the price to the patients but will

 

      patients be disaffected or unable to get the

 

      medicine if there is a price differential.

 

                We didn't build that in as an explicit

 

      consideration, the cost issue, but it was mentioned

 

      in the preamble because many of the comments to the

 

      ANPR and to the PR as we developed this re-write of

 

      2.125, brought up the issue of affordability.

 

                Now, specific to albuterol which

 

      has--actually, this should say one branded product

 

      available and three generics marketed--for moieties

 

      with more than one available product or strength

 

      such as albuterol, you would need at least two

 

      non-ozone-depleting-substance products with the

 

      same active moiety, the same indication, route of

 

      administration, about the same level of

 

      convenience, and the other criteria were the same.

 

                So, in other words, if the moiety was

 

      represented in the marketplace by different

 

                                                                32

 

      strengths or different numbers of products from

 

      different manufacturers, we felt it important that

 

      there be sort of at least--if not a full match to

 

      the range, at least alternatives that represented

 

      some choice.

 

                Let me just show you, to wrap up this

 

      background, where all this has led over time.  This

 

      is a graph of the global situation for CFC

 

      essential uses.  Let me go through the two lines

 

      here.  This is 1996.  The open space is actually

 

      the year, not the hatch mark, so we go from 1996

 

      out to 2006 on the X axis.  On the Y axis, we are

 

      talking about metric tons.  A metric ton is 2200

 

      pounds, so these are metric tons of total CFC used

 

      for essential-use allowances in these developed

 

      countries.

 

                The red line is the amount that was

 

      exempted--in other words, the amount that was

 

      nominated and approved by the parties.  The blue

 

      line is the amount that was actually used over

 

      time.  The green line is the stockpiles.  So these

 

      are the amounts held by the countries that don't

 

                                                                33

 

      represent new production.

 

                You can see that the peak of the use

 

      worldwide, or at least in these developed countries

 

      that were putting in essential uses, was just about

 

      9,000 metric tons occurring in the 1997-1998 range.

 

      This has fallen by 2003 down to just a little bit

 

      over 4,000 tons.  One would project from the amount

 

      nominated, which generally has been historically

 

      higher than the amounts actually used, that this

 

      will further fall in the coming two years rather

 

      dramatically.  So the amounts nominated in 2006 are

 

      down below 3,000 metric tons.

 

                I apologize for this being a little harder

 

      to see.  I could not manipulate this as easily as

 

      the last one.  But this is the situation for the

 

      United States, itself.  Again, this is metric tons

 

      per year on the Y axis, years on the X axis.  I

 

      know that will be very difficult for people in the

 

      audience to see but the main point here is this is

 

      the blue line, which is the amount used for

 

      metered-dose inhalers in the United States.

 

                You can see, for the most part, that it

 

                                                                34

 

      has been reasonable stable from the

 

      pre-Montreal-Protocol years through the time period

 

      of the Montreal Protocol, although there was a

 

      rather substantial fall in the last couple of

 

      years--this goes out to 2002--at which time the

 

      total use was just a little bit over 1500 metric

 

      tons in the United States.  I would point out that

 

      the use for albuterol is a substantial portion of

 

      the United States nomination.

 

                Let me also now talk about the transition

 

      within the United States, itself.  What we have

 

      here is a slide that attempts to display the

 

      original listings under the 2.125 and then the

 

      specific listings under 2.125, and then to display

 

      changes over time.

 

                So, originally, 2.125 had the broad class

 

      of beta-adrenergic agents: inhaled corticosteroids;

 

      nasal steroids; the cromones--cromolyn and

 

      nedocromil were actually separately listed;

 

      ipratropium; atropine, which was actually approved

 

      for use in Desert Storm; a combination product,

 

      albuterol and ipratropium.

 

                                                                35

 

                I think it is important for me to point

 

      out, if Dr. Sullivan does not and if it is

 

      repeated, I think it is still and important thing;

 

      we are not talking about a combination product

 

      today.  We are only talking about those products

 

      that solely contain albuterol as their active

 

      ingredient; and then a number of other products,

 

      many of which were actually, as you can see, not

 

      MDIs.  So we had talc, contraceptive foams, rectal

 

      foams, ergotamine MDIs, polymxin, anesthetic drugs

 

      including those that directly use CFCs, and

 

      nitroglycerine.

 

                When the re-write of 2.125 was finalized

 

      in 2002, those products listed in red were taken

 

      out, many of these because they either did not meet

 

      the criteria any longer or  were not considered

 

      essential under the Montreal Protocol, or they were

 

      no longer marketed.

 

                So, at the time of the finalization,

 

      isoetharine, isoproterenol, the nasal steroids as a

 

      class, contraceptive foams, rectal foams, polymyxin

 

      and nitroglycerine all came out and were not

 

                                                                36

 

      separately listed in 2.125.

 

                The products in yellow could be considered

 

      as potential for delisting soon, these because they

 

      are no longer available, marketed as CFC products.

 

      One of the things in 2.125 re-write that was said

 

      was that, if a product was not marketed for a

 

      substantial period of time, one could consider it

 

      to be not essential.  Those would include

 

      bitolterol, salmeterol, which was discontinued by

 

      the manufacturer, dexamethasone, talc, ergotamine

 

      MDIs and anesthetic drugs.

 

                Beclomethasone is no longer marketed, the

 

      MDIs, at least not newly produced MDIs, and there

 

      are alternatives.  So that is another potential

 

      delisting.  Albuterol, I guess I did not put in

 

      yellow here because that is what we are here to

 

      discuss today is whether that has met the criteria

 

      that we laid out in the revisions of 2.125.

 

                So, to conclude my talk, the U.S.

 

      Government moved proactively to address the issue

 

      of ozone depletion shortly after the development of

 

      the ozone science, and the U.S. Government had a

 

                                                                37

 

      key role in the formation and the conduct of the

 

      Montreal Protocol.  The Montreal Protocol is

 

      considered a successful treaty that has led to

 

      important reductions in CFCs and other

 

      ozone-depleting substances and, as I mentioned,

 

      there are data to suggest that the recovery of the

 

      stratospheric ozone layer is in the early stages.

 

                Now, the Montreal Protocol, as I pointed

 

      out from the evolution of some of the decisions

 

      taken, is increasingly moving towards control in

 

      its specific essential uses, notable amongst those

 

      would be albuterol.

 

                Just as a transition slide, I chose

 

      another picture off the NASA web page of the ozone

 

      depletion.  Remember that I said we would recover

 

      to the early '80's levels by the mid part of this

 

      century.  This shows the Antarctic region in 1983

 

      and the Antarctic region in 1993.  You can see the

 

      difference where the white is the thicker ozone.

 

      You can see the difference in the ozone layer in

 

      that decade.

 

                So, thank you very much.

 

                                                                38

 

                DR. CHINCHILLI:  Thank you, Dr. Meyer.

 

                You finished a few minutes early so let's

 

      see if there are any questions from our committee

 

      members.   I have one, Dr. Meyer.  What was the

 

      rationale behind the decision about not pursuing

 

      this with the--not considering the dry-powdered

 

      inhalers as a similar moiety?

 

                DR. MEYER:  What we said was that we

 

      thought they could serve as an alternative but it

 

      would not be as automatic as an MDI.  So, in fact,

 

      I think if there were an albuterol dry-powdered

 

      inhaler that met those criteria otherwise, we would

 

      consider it.

 

                I think, at the time we were writing it,

 

      we had considerations such as, at that point,

 

      albuterol was available in a capsule, an individual

 

      capsule, rotohaler-type device where one would

 

      place it in, turn it and breathe.  We did not feel

 

      that that had sort of the same level of convenience

 

      and portability and so on as an MDI.  So I think we

 

      wanted to not exclude all dry-powdered inhalers out

 

      of hand but say that they would have to meet

 

                                                                39

 

      certain levels of convenience and patient

 

      acceptability.

 

                Again, the presumption in the preamble to

 

      rule was that the MDIs would most neatly do that

 

      because they are very much similar.

 

                DR. CHINCHILLI:  Dr. Martinez?

 

                DR. MARTINEZ:  Dr. Meyer, in your

 

      multicolored slide, there was some products in

 

      white.  I presume those will continue to be

 

      available by way of CFCs and includes epinephrine,

 

      for example; is that correct?

 

                DR. MEYER:  Some of those products in

 

      white are, in fact, under development in that are

 

      alternatives being developed.  Some are not.  One

 

      of the provisions in the rule that I didn't bring

 

      up today because it wasn't fully germane but I

 

      would be happy to answer as a part of your question

 

      is the fact that, beginning next year, we will have

 

      the ability to call this body into meetings, have

 

      the advisory committee come to meetings, to discuss

 

      those products that remain on the list that are not

 

      being reformulated and whether they remain

 

                                                                40

 

      essential.

 

                I think, just parenthetically, epinephrine

 

      will be something that will be important for us to

 

      discuss at some time in the future.

 

                DR. CHINCHILLI:  Any other questions from

 

      the committee?  If not, thank you, again, Dr.

 

      Meyer.

 

                I guess we will move forward with Dr.

 

      Sullivan, the Deputy Director of the Division of

 

      Pulmonary Drug Products.

 

                         Medical Considerations

 

                DR. SULLIVAN:  Good morning.  I am Gene

 

      Sullivan.  I am a pulmonologist.  I am also the

 

      Deputy Director of the Division of Pulmonary and

 

      Allergy Drug Products at FDA.  For the next twenty

 

      or thirty minutes, I am going to be discussing some

 

      of the medical considerations in regard to this

 

      proposal to remove albuterol from the list of drug

 

      substances that are considered essential uses for

 

      CFCs.

 

                Following my talk, you will hear from Dr.

 

      Lutter, as Dr. Meyer mentioned.  Dr. Lutter will go

 

                                                                41

 

      into more depth in regard to the economic aspects

 

      of this question.  Then, following that, you will

 

      hear some very important information from

 

      interested parties who will be speaking during the

 

      open public hearing.

 

                So this slide provides a background

 

      overview of my talk.  Dr. Meyer has just given a

 

      very nice background on the overarching issues

 

      about the Montreal Protocol and the FDA Regulation

 

      2.125, so my background remarks will be brief.

 

      Then, also, briefly, I will review the currently

 

      marketed albuterol MDI products.  But the bulk of

 

      my talk will be in this section specifically

 

      looking at the criteria that Dr. Meyer mentioned

 

      that are included in the Amended 2.125, so the

 

      currently existing regulation, and specifically

 

      examining those criteria in regard to how they

 

      apply in the case of albuterol.

 

                Then, finally, I will touch on a couple of

 

      other issues which, although they are not directly

 

      responsive to the criteria laid out in 2.125, I

 

      think are clearly important issues to consider when

 

                                                                42

 

      deciding on a path forward with regard to

 

      albuterol.

 

                So, again, Dr. Meyer has provided very

 

      nice background on the Montreal Protocol and on the

 

      FDA regulation concerning the essential-use

 

      determinations, that being 21 CFR 2.125 and, as Dr.

 

      Meyer mentioned, I will be referring to it as 2.125

 

      from now on.

 

                As you know, the agency is currently

 

      considering whether albuterol, in fact, has met the

 

      criteria that are listed in 2.125 for removal from

 

      the list of essential uses.  This process that we

 

      are embarking on is in keeping with the goals of

 

      the Montreal Protocol, specifically, the goal of

 

      phasing out production and importation of

 

      ozone-depleting substances including

 

      chlorofluorocarbons.

 

                I think the step forward with albuterol is

 

      an important step in that direction particularly

 

      because approximately half of the annual

 

      essential-use CFC allocation in the U.S. is for

 

      albuterol.  We are moving forward in this direction

 

                                                                43

 

      in light of the fact that there now exist two

 

      alternative, non-CFC albuterol metered-dose

 

      inhalers on the market in the U.S., that being

 

      Proventil HFA and Ventolin HFA.

 

                In addition, in 2003, the American Lung

 

      Association submitted a citizen petition on behalf

 

      of a group of organizations, collectively referred

 

      to as the U.S. Stakeholders Group.  That petition

 

      requested that the agency move forward with this

 

      rulemaking process in order to remove albuterol

 

      from this list.

 

                That citizen petition is included in your

 

      background materials.  Your background materials

 

      also include other communications we received from

 

      the Stakeholder's Group as well as the submissions

 

      to the public docket that were submitted by various

 

      interested parties and organizations in response of

 

      the citizen petition.

 

                So what are the currently marketed

 

      albuterol metered-dose inhalers?  Obviously, they

 

      can be divided into those that contain CFCs, which

 

      are ozone-depleting substances, and those that

 

                                                                44

 

      don't contain CFCs.  In terms of the CFC MDIs,

 

      there are several.  First of all, there is the

 

      branded product, Proventil, marketed by

 

      Schering-Plough.  This was approved in 1981.  In

 

      addition, there is a product marketed under a

 

      Warrick label which is marketed under the same NDA.

 

                Then there are several generic versions.

 

      Actually, four have been approved.  The first of

 

      these was approved in 1995.  Currently, three of

 

      these are being marketed.  As you may know, in

 

      1981, there were actually two branded albuterol CFC

 

      MDIs that were approved, the other one being

 

      Ventolin.  That is not listed here because it is no

 

      longer marketed within the U.S.

 

                Now moving to the non-CFC MDIs or, and I

 

      will use the shorthand, as alternatives, these

 

      don't use CFCs.  Rather they use HFA 134A which is

 

      a substance that does not affect the ozone layer.

 

      There are two of these HFA products; Proventil HFA,

 

      which was approved and initially marketed in 1996

 

      and, more recently, Ventolin HFA, which was

 

      approved in 2001 and was marketed in 2002.

 

                                                                45

 

                So this is the regulation, obviously, that

 

      is at the heart of today's discussion, 2.125,

 

      called the Use of Ozone Depleting Substances in

 

      Food, Drugs, Devices or Cosmetics.  Among a number

 

      of thing, one of the things that it does is it

 

      lists specific drug moieties for which the use of

 

      CFCs is considered essential.

 

                In addition, as Dr. Meyer mentioned, it

 

      sets forth criteria.  There are four such criteria

 

      that must be met in order to remove a drug moiety

 

      from the list of essential uses.

 

                I will run through these again.  Dr. Meyer

 

      has been through them.  I will run through again,

 

      though, because I think they are the heart of

 

      today's discussion.  First of all, and here I am

 

      referring to active moieties represented by two or

 

      more NDAs which is the case, as I mentioned, with

 

      albuterol.

 

                The first criterion for removing a drug

 

      from the list of essential uses would be that at

 

      least two non-ozone-depleting-substance products

 

      that contain the same active moiety are being

 

                                                                46

 

      marketed with the same route of delivery for the

 

      same indication with approximately the same level

 

      of convenience as the ozone-depleting product.

 

                The second criterion is that supplies and

 

      production capacity for the alterative must exist

 

      or be expected to exist at levels that would be

 

      sufficient to meet patient need.

 

                The third criterion is that adequate

 

      postmarketing-use data should be available for the

 

      non-ozone-depleting products.  Again, as Dr. Meyer

 

      mentioned, that is to provide some reasonable

 

      assurance that no unanticipated limitation of the

 

      alternative product emerges during the

 

      postmarketing, so real-world experience that was

 

      not detected prior to approval.

 

                Then, finally, the fourth criterion is

 

      that patients who medically require the product

 

      would be adequately served by non-ozone-depleting

 

      products containing the same active moiety and

 

      other available products.

 

                So now I am going to walk through each of

 

      these criteria and look at how they apply to

 

                                                                47

 

      albuterol.  The first criterion; again, at least

 

      two products containing the same active moiety, the

 

      same route of delivery, the same indication and

 

      approximately the same convenience of use.  So,

 

      clearly, the alternatives that we are discussing,

 

      Ventolin HFA and Proventil HFA, both have the same

 

      active moiety, albuterol.  Both are delivered by

 

      the same route of delivery, oral inhalation, and

 

      carry the same indication, prevention and relief of

 

      bronchospasm and patients with reversible

 

      obstructive airway disease and prevention of

 

      exercise-induced bronchospasm.

 

                I should point out the initial NDA,

 

      Proventil, was approved down to the age of 12 and

 

      Ventolin was approved down to the age of four.

 

      Both of the alternative products are approved down

 

      to the age of four.

 

                Finishing up with the first criterion, the

 

      final bit of it is the same level of convenience.

 

      Now, when we looked at the same level of

 

      convenience, we described, in the Preamble, various

 

      aspects of what we might mean by that.  We looked

 

                                                                48

 

      at things like portability, preparation before use

 

      and the physical effort of manual dexterity that

 

      might  be needed to administer the drug.

 

                The CFC and HFA MDIs are quite similar and

 

      so have very similar portability and require

 

      similar degrees of physical effort and dexterity to

 

      use.  I should mention, in regard to preparation

 

      before use, that, in the early experience with the

 

      first HFA that was approved, the Proventil HFA, we

 

      became aware that there were occasional instances

 

      of clogging of the actuator if they were not

 

      cleaned properly.

 

                Now, the CFC and the HFA inhalers have

 

      actually very similar cleaning instructions.  It is

 

      just evident that patients using the HFA inhalers

 

      need to pay more attention to the cleaning

 

      instructions that are already in the label for both

 

      products.

 

                The second criterion is a little bit more

 

      difficult to definitively establish at this point.

 

      This is the criterion that states that supplies and

 

      production capacity for the alternatives need to be

 

                                                                49

 

      at levels that would be sufficient to meet patient

 

      needs.  At least in part, because of the price

 

      differential between the generics and the currently

 

      marketed FHA products, the market share for the HFA

 

      products, at this point in time, is much smaller in

 

      comparison than the market share of the CFC

 

      products.

 

                So, if the CFC products were to become

 

      unavailable suddenly today, the current supplies

 

      and production capacity of the HFA alternatives are

 

      not sufficient to meet patient need.  That is

 

      because, simply, that the manufacturers would need

 

      time to ramp up production.  However,

 

      GlaxoSmithKline, in its statement in response to

 

      the citizen petition submitted to the docket and

 

      included in your background package has stated that

 

      it is confident that additional internal and

 

      external capacity can be installed to insure

 

      adequate supplied and production capacity for

 

      Ventolin HFA and that this could be accomplished

 

      within twelve to eighteen months.

 

                In addition to this statement in the

 

                                                                50

 

      docket, GlaxoSmithKline and, also, Schering-Plough,

 

      will be speaking today and I expect that at least a

 

      portion of their comments may address specifically

 

      this criterion.

 

                The third criterion that we are applying

 

      is that adequate U.S. postmarketing data be

 

      available for the alternatives, again, looking for

 

      unexpected real-world problems with the

 

      alternatives.  At this point in time, we have

 

      Proventil HFA which has been marketed for seven

 

      years and Ventolin HFA which has been marketed for

 

      two years.

 

                Apart from the early reports of actuator

 

      clogging that I mentioned, the available

 

      postmarketing use data does not suggest any

 

      problems in terms of safety, efficacy, tolerability

 

      or patient acceptance of these two alternatives.

 

                Perhaps the most difficult of the criteria

 

      to address is the fourth.  This is the criterion

 

      that states that patients who medically require the

 

      ODS are adequately served by the alternative.  This

 

      term, "adequately served," is fairly broad and it

 

                                                                51

 

      encompasses a number of things.

 

                Clearly, the most important is that the

 

      available data on the alternatives must demonstrate

 

      sufficient efficacy and safety and tolerability and

 

      so forth such that the alternatives could be

 

      considered reasonable replacements for the CFC

 

      MDIs.  This type of data was submitted with the NDA

 

      and has accumulated in a postmarketing period and

 

      seems to imply that the alternatives do meet these

 

      criteria.

 

                But there is a further subtlety to the

 

      adequately served phrase here and that is cost.  As

 

      Dr. Meyer mentioned, during the process of the ANPR

 

      and the proposed rule, there were comments about

 

      the effect of this rule on the price of

 

      medications.  In the Preamble, in the Federal

 

      Register, the Preamble to the 2002 Amendment where

 

      these criteria were established, the FDA clearly

 

      stated that it will consider cost in determining

 

      whether the alternatives meet patient needs.

 

                So I am going to take a couple more slides

 

      to just look at this cost issue a little bit in

 

                                                                52

 

      more depth.  As with most drugs, branded CFC

 

      products cost more than their generic counterparts.

 

      As it turns out, in this very complicated

 

      healthcare system that we have in the U.S. in which

 

      the specific price of a medication varies according

 

      to a number of factors including who is paying, it

 

      is somewhat difficult to arrive at "the" price of a

 

      drug.

 

                Therefore, it is somewhat difficult to

 

      arrive at a clear statement of the differential

 

      between the cost of a branded product and a generic

 

      product.  Dr. Lutter will go into this in a little

 

      bit more depth and talk about the various sources

 

      of data that are available for the price of a

 

      medication and how complicated that issue is.

 

                I have provided on this slide some data

 

      from an FDA website that highlights the cost

 

      savings to a patient that can be achieved with

 

      generic products.  The web address is in your

 

      handouts.  On this site, data on the average

 

      national retail price, which was data from IMS

 

      Health, were used to generate this information so

 

                                                                53

 

      that the retail cost per day for an asthmatic

 

      patient who used Ventolin would be $1.44 whereas

 

      the CFC generic would be 69 cents per day.

 

                Of course, this is a comparison between a

 

      CFC generic and a CFC branded, so it is important

 

      to note the branded HFAs, in general, are priced

 

      comparably to the branded CFC products although not

 

      exactly the same price.

 

                The other element to this is that there

 

      are a number of existing patents and, due to these

 

      patents, there are currently no generic HFA

 

      products available.  These patents are listed to

 

      expire, the first one in 2010 and the final patent

 

      in 2015.  So, given the current realities, the

 

      removal of the essential-use status of albuterol

 

      would result in an increase in the price of

 

      albuterol MDIs.

 

                The public-health consequences of such an

 

      increase in price are not known and are, in fact,

 

      very difficult to predict.  One possibility would

 

      be that patients who are prescribed albuterol

 

      metered-dose inhalers may be either unable or

 

                                                                54

 

      unwilling to pay for that and so may not purchase

 

      the albuterol inhalers.

 

                It is also possible that an increase in

 

      the price of an albuterol MDI, which is an

 

      acute-reliever drug from which patients, as you

 

      know, perceive an immediate benefit, might result

 

      in them forgoing filling prescriptions of other

 

      medications such as asthma-controller drugs from

 

      which they don't receive the same immediate

 

      feedback.  But, as you know, controller drugs are

 

      quite important in the appropriate management of

 

      asthma.

 

                So, as I mentioned, Dr. Lutter will

 

      discuss in greater depth these economic aspects

 

      including descriptions of the various sources of

 

      price data that are available and means for

 

      estimating how changes in the price of albuterol

 

      MDI might affect the utilization.

 

                As I mentioned, that is a difficult task

 

      in and of itself, how will an increase in price of

 

      an MDI translate into a change in utilization of

 

      albuterol and, even if we were able to establish

 

                                                                55

 

      that firmly, the next question that begs answering

 

      would be how does the change in utilization

 

      translate into important health outcomes.  Of

 

      course, that is an open question as well.

 

                So, before I close, as I mentioned, I want

 

      to bring up a couple of other issues that are not

 

      directly responsive to the criteria in 2.125 but,

 

      nonetheless, may be quite important in

 

      considerations regarding a path forward on

 

      albuterol.  Both of these issues relate to the

 

      future availability of chlorofluorocarbons.

 

                The first issue has to do with production

 

      facilities.  Currently, the only source of

 

      pharmaceutical-grade CFC 11 and 12 for use in the

 

      U.S. is Honeywell's plant in the Netherlands.  CFC

 

      11 and 12 are the particular chlorofluorocarbons

 

      that are contained in the albuterol CFC MDIs.

 

                The Dutch Government has informed

 

      Honeywell that CFC production at that factory will

 

      no longer be permitted after 2005.  So that might

 

      jeopardize the supply of CFCs that are necessary

 

      for the manufacture of albuterol MDIs but also all

 

                                                                56

 

      of the other MDIs that use pharmaceutical-grade

 

      CFCs.  However, Honeywell has stated in its

 

      submission to the docket in response to the citizen

 

      petition that it will begin production of

 

      pharmaceutical-grade CFC 11 and 12 at a U.S. plant

 

      and will be able to supply CFCs beyond 2005.

 

      Honeywell will also be speaking during the open

 

      public hearing session today.

 

                The second issue that touches on the

 

      future availability of the CFCs refers to potential

 

      actions that might be taken by the parties to the

 

      Montreal Protocol.  So, as Dr. Meyer mentioned,

 

      each year the U.S. and other countries who request

 

      to manufacture CFC MDIs, go through a nomination

 

      process whereby specific quantities of CFCs are

 

      requested of the parties.

 

                Thus far, the parties have respected the

 

      U.S. determination that albuterol is, in fact,

 

      essential and have granted the volumes requested by

 

      the U.S.  However, more recently, the parties have

 

      very pointed noted the availability of two non-CFC

 

      alternatives within the U.S. and some have

 

                                                                57

 

      questioned the continued need for

 

      chlorofluorocarbons for this purpose.  It is not at

 

      all clear how long the parties will continue to

 

      grant CFC requests for use in albuterol MDIs.

 

                So, with that, I will close.  I have

 

      listed on this slide the questions or topics for

 

      discussion that have  been provided to you in a

 

      handout format.  Essentially, the agency is asking

 

      you to discuss the extent to which you believe the

 

      criteria that are established in the 2.125 for

 

      removal of a drug substance from the list of

 

      essential uses of CFCs have been met in the case of

 

      albuterol.  Beyond that, we are open to hearing

 

      from you any suggestions of additional data,

 

      additional information or other issues you think

 

      should be considered as we move forward in this

 

      process of determining the essential-use status of

 

      albuterol.

 

                With that, I will close.

 

                DR. CHINCHILLI:  Thank you, Dr. Sullivan.

 

      Again, we are ahead of schedule so we can take some

 

      questions from committee members if there are any

 

                                                                58

 

      questions.  Yes, Dr. Atkinson?

 

                DR. ATKINSON:  Can you comment on whether

 

      the existence of the patents on the new HFA devices

 

      are going to preclude the development of any

 

      generics until that time period?  Are there any

 

      pending applications for generic devices?

 

                DR. SULLIVAN:  Of course, we can't comment

 

      on any pending applications.  The analysis of

 

      patents is a complex issue that the FDA doesn't

 

      really directly do.  Companies claim they have

 

      patents which protect them.  If a generic firm

 

      wants to challenge that patent, they can.  I think,

 

      beyond that, perhaps I will invite Wayne Mitchell

 

      to comment more specifically, if he can.

 

                MR. MITCHELL:  I really can't say much

 

      more.  We don't have any institutional expertise on

 

      patent law.  Patents are listed in our Orange Book.

 

      The patents are listed through 2015.  That is about

 

      all we really can say.

 

                DR. CHINCHILLI:  Any other questions?  Dr.

 

      Sullivan, I have a question.  In one of your

 

      slides, when you talked about Proventil HFA, you

 

                                                                59

 

      said that early reports of actuator clogging were

 

      available.  Does that imply that there are no

 

      longer reports of this problem?  Were there

 

      modifications to the device?  I just was confused

 

      by the word "early" reports of actuator clogging.

 

                DR. SULLIVAN:  That refers to the fact

 

      that when the product first went on the market--and

 

      it is not unusual to get more reports on a

 

      particular drug when it first hits the market, but

 

      the agency became aware that patients were having

 

      problems with the clogging of the actuator and an

 

      effort was made to better publicize the necessity

 

      of cleaning these products because, although the

 

      cleaning instructions were included in the CFC

 

      versions, they may not have been followed by

 

      patients.

 

                It was determined that if the instructions

 

      are actually followed, there are fewer reports.  I

 

      believe that the number of such reports has

 

      declined.  That was sort of an early phenomenon.

 

                DR. CHINCHILLI:  Thank you.  Any other

 

      questions?  Okay; if not, then we will move on to

 

                                                                60

 

      Dr. Lutter.

 

                        Economic Considerations

 

                DR. LUTTER:  My name is Randy Lutter.  I

 

      manage a small economics group within the Office of

 

      Policy and Planning, Office of the Commissioner at

 

      FDA.  It is my pleasure to be here.

 

                I would like to talk to you today about

 

      the question of whether or not delisting albuterol

 

      will have effects on--whether the patients will be

 

      adequately served by delisting albuterol.

 

                Let me begin by giving you an overview.

 

      The key conclusion is that delisting albuterol CFCs

 

      will deter the use of a number of prescribed MDIs

 

      that is large in absolute terms but small relative

 

      to the market.  Our analysis is ignoring an

 

      announced giveaway by GlaxoSmithKline of 2 million

 

      MDIs per year because we lack a basis to evaluate

 

      that quantitatively.  We also find that the effects

 

      on public health are too uncertain to quantify.

 

                Let me give you some brief institutional

 

      background of how an economist ends up in the

 

      position of speaking before a group of esteemed

 

                                                                61

 

      pulmonary and allergy advisors to FDA.  There is an

 

      executive order, 12866, signed by President Clinton

 

      in '93 and it actually follows one signed by

 

      President Reagan in '81.  It directs the agencies

 

      to assess the costs and benefits of all regulatory

 

      actions developed through the notice and comment

 

      rulemaking that Dr. Meyer described earlier.

 

                The office that I had at FDA develops the

 

      economic analyses required by that executive order.

 

      The method of economic analysis that we developed

 

      follows the constraints of OMB Circular A-IV which

 

      is the latest in a series of circulars developed by

 

      the Federal Office of Management and Budget

 

      directing agencies on how to conduct economic

 

      analyses.

 

                The executive order directs agencies to

 

      assess the cost and the benefits and to take

 

      regulatory actions which are cost-effective but

 

      economics also is reflected in the decisions of the

 

      Montreal Protocol.  Drs. Meyer and Sullivan have

 

      mentioned the term "essential," and "essential

 

      use," turns on whether there are available

 

                                                                62

 

      technically and economically feasible alternatives

 

      or substitutes that are acceptable from the

 

      standpoint of environment and health and that is in

 

      Decision IV-25.  Section 2.125 uses the phrase

 

      "adequately served."  As described by Dr. Meyer,

 

      that has economic content.

 

                So there are actually three institutional

 

      reasons why economics matters for the current

 

      decision.

 

                A brief discussion of economic

 

      fundamentals.  The issue here is that delisting

 

      would remove albuterol MDIs with CFCs.  Those are

 

      currently the only generic albuterol MDIs on the

 

      market.  Therefore, one would anticipate on that

 

      basis an increase in the price.  So the broad

 

      question is whether or not that increase in price

 

      has effects on whether or not patients are

 

      adequately served.

 

                To comply with the executive order, we

 

      need to assess the benefits of delisting and, in

 

      particularly, a relatively earlier delisting as

 

      opposed to a later one, and also the costs of

 

                                                                63

 

      earlier delisting.

 

                The benefits come in four separable

 

      categories.  The first is a controlled transition.

 

      You have already heard presentations about the

 

      nature of the international cooperation and the way

 

      that that might affect the availability of CFCs by

 

      offering a relatively--by proceeding with this

 

      rulemaking, FDA hopes to establish an opportunity

 

      for a controlled transition to CFC-free MDIs.

 

                The second category of benefits is clearly

 

      the environmental ones that Dr. Meyer has

 

      described.  Reduced emissions would lead to

 

      reductions in skin cancers, cataracts and

 

      UVB-related ecological benefits.  For this, our

 

      proposal, FDA has not been able to quantify the

 

      benefits in terms of skin cancers, cataracts or

 

      UVB-related ecological benefits.

 

                Some analysis in quantitative terms has

 

      been conducted previously by other federal agencies

 

      including the EPA.  The difficulty that we face is

 

      in translating their estimates of aggregate

 

      benefits to the benefits from the much smaller

 

                                                                64

 

      reductions of CFC emissions that might be achieved

 

      from this rulemaking, and we haven't been able to

 

      do that for this proposal.

 

                A fourth category of benefits pertains to

 

      international cooperation.  Dr. Meyer did not

 

      understate in any way the importance of the

 

      Montreal Protocol.  It is a flagship treaty for

 

      successful international environmental protection

 

      and it enjoys wide respect and esteem for that

 

      reason.

 

                A final category of benefits is that this

 

      rulemaking may encourage innovation in

 

      environmental safe technologies.

 

                In terms of the costs, I would like not to

 

      focus on the increased spending associated with a

 

      higher price of MDIs but, instead, focus on a

 

      related question of whether or not the increased

 

      prices may deter appropriate usage.  I think that

 

      is the appropriate issue for this panel and that is

 

      the one that I am going to devote the rest of my

 

      time to.

 

                Also, by way of background in economics, a

 

                                                                65

 

      key notion is what are we comparing the world to

 

      when we do our analysis.  We need to describe what

 

      is the baseline relative to which we are assessing

 

      the effects of delisting.  The baseline in this

 

      instance is the continued availability of generic

 

      CFC albuterol.  So the analysis that we are

 

      conducting is relative to a world in which the CFC

 

      albuterols continue to be available and, therefore,

 

      the generic CFCs also continue to be available.

 

                What I am going to focus on is a

 

      relatively standard and conventional economist

 

      approach to estimating the response to higher

 

      prices.  It really focuses, in particular, on the

 

      estimated quantity of metered-dose inhalers that

 

      may not be consumed as a result of the increased

 

      price.    It interprets this as the

 

      product, really, of three things.  One is the price

 

      increase in percentage terms.  The other one is a

 

      measure of the consumer sensitivity to the price

 

      increase, a measure the economists typically

 

      describe using the word "elasticity," and, lastly,

 

      the MDIs sold in the baseline to price-sensitive

 

                                                                66

 

      consumers.  So these are three parameters that I

 

      will draw your attention to.

 

                With respect to the price increase, the

 

      prices are, of course, variable in a particular

 

      way.  The vary with market conditions and they vary

 

      also in response to the marketing decisions made by

 

      the different companies marketing the products.  As

 

      a result, the assessments of the price are

 

      difficult not only because of the data deficiencies

 

      but also because, ideally, we need to be looking

 

      forward to what the price difference might be

 

      between a world where the albuterol CFCs are

 

      delisting and a world where they would continue to

 

      be available.

 

                That forward-looking approach requires and

 

      association of these prices that takes the

 

      variability into account.  For the purposes of our

 

      analysis, that is too complicated and we are,

 

      instead, going to take the current price

 

      differences as a measure of the price increases

 

      from the delisting.  The merits of this approach

 

      are simplicity, transparency and also consistency

 

                                                                67

 

      with an announced policy of GSK that it would

 

      freeze wholesale prices through December, 2007.

 

                Where does one go for information on

 

      prices?  In the modern day, Google comes to mind as

 

      a source of all information.  If you go to Google

 

      and look for prices, you come to drugstore.com.  It

 

      listed generic MDIs with albuterol on the 24th of

 

      March for $14.  HFA at drugstore.com sold a

 

      Proventil.  The Proventil HFA was sold at $39.61

 

      and Ventolin HFA sold at $38.99.  Those prices I

 

      have checked twice and they were relatively

 

      unchanged in the recent period.

 

                That gives an increase of about 180

 

      percent just comparing the generics to the HFA.

 

      But these web-based prices are really

 

      unrepresentative.  They neglect the

 

      brick-and-mortar outlets.  They neglect shipping

 

      costs.  Ideally, what one would want are average

 

      retail market prices for the cash-paying customers

 

      who would be sensitive to price increases.

 

                We have not acquired these idea data for

 

      the analysis that we have conducted for this

 

                                                                68

 

      proposal.  So, instead, I am going to talk to you

 

      about data we have acquired which are the best

 

      available proxies at this moment.

 

                The Medical Expenditure Panel Survey of

 

      the Agency for Healthcare Research and Quality

 

      provides some information on prices.  This survey

 

      assesses expenditures by the noninstitutionalized

 

      people age less than 65 in the non-Medicare

 

      population.  It provides information on the average

 

      retail prices among all payer types, the insured

 

      and the uninsured alike, for CFC albuterol inhaler

 

      prescriptions 2000 to 2001.

 

                The information is that the generics are a

 

      little bit less than $25.  I also report here the

 

      standard error.  The brand is $39.  You have heard

 

      Professor Sullivan mention that the branded price

 

      of the CFC tends to be close to the branded price

 

      of the HFA.  In this instance, the data on the HFA

 

      prices are too rare to report.

 

                We also looked using the MEPS survey at a

 

      sensitive population that lacks insurance or has

 

      only private non-group insurance which, in the

 

                                                                69

 

      judgment of experts at ARC would typically exclude

 

      coverage for drugs.  We looked among this group at

 

      people with incomes less than 400 percent of the

 

      federal poverty level.  This was a convenient

 

      cutoff, given the data constraints of MEPS.

 

                Within this group, the estimated average

 

      retail prices were $22 for the generic inhalers

 

      and, again, in this instance, the data on the

 

      branded inhaler prices were too rare to be

 

      reportable.  This group had about 2.8 million

 

      albuterol prescriptions annually.

 

                A second source of data on prices that we

 

      consulted is proprietary information from IMS

 

      Health, their national prescription audit for the

 

      first quarter of 2004.  Note the distinction in

 

      dates.  The MEPS is 2000-2001 and this is 2004.

 

      There is no more recent information on MEPS.  For

 

      the IMS price information, we have prices measured

 

      using the average pharmacy's revenues from

 

      uninsured customers, insured customer and Medicaid

 

      beneficiaries alike.  So this is basically across

 

      all payer types.

 

                                                                70

 

                This includes chain, independent,

 

      food-store pharmacies.  It excludes the Internet.

 

      It excludes mail-order and long-term-care

 

      pharmacies.

 

                Information on prices from IMS suggests

 

      that the median price for the generic albuterol

 

      MDIs is $19.70 and for the albuterol HFA MDIs, the

 

      price is $43.00, the price difference of about

 

      $23.00.  This suggests an increase of about 120

 

      percent.

 

                It is important to view these data as

 

      approximate for a variety of reasons.  I have

 

      acknowledged the proxies for the conceptually

 

      correct measure.  In addition, the HFA prices have

 

      been changing.  The MDI data suggests that there

 

      has been an increase of about 18 percent over the

 

      twelve months preceding the sample of the first

 

      quarter in 2004.  Again, these prices reflect the

 

      full price for the insured and the uninsured alike.

 

                The next part of the puzzle is to assess

 

      the response to the increase in price that one

 

      might expect among consumers.  In general, there is

 

                                                                71

 

      an extensive economics literature that reports

 

      small effects of price increases on consumption.

 

      It rarely distinguishes, however, among drugs.

 

      There is a very recent article by Dana Goldman of

 

      Rand in JAMA that surveys more than a half million

 

      people in 52 health plans over four years.

 

                interestingly, it reports responses to

 

      increases in co-pay among different categories of

 

      medicines.  With respect to anti-asthmatics, as the

 

      average co-pay for anti-asthmatics doubles, the

 

      average number of days of treatment supplied fell

 

      by more than 30 percent.  The authors report that

 

      albuterol was the most common anti-asthmatic

 

      including albuterol sulfate.

 

                They also assess the effects on public

 

      health.  Let me back up a moment.  They also assess

 

      for drugs with no OTC substitutes, the set that

 

      presumably includes albuterol MDIs.  The response

 

      in utilization described as I just did in the

 

      average number of days of treatment supplied is

 

      0.15.  So there is substantial uncertainty about

 

      what would be the relevant number.

 

                                                                72

 

                With respect to average co-pay for

 

      anti-asthmatics as a group, the response is 0.3.

 

      But, if one then looks at drugs with no OTC

 

      substitutes which would also include albuterol, the

 

      effect is 0.15.

 

                The authors go on to talk about the effect

 

      of these increases in co-pay on ER visits and on

 

      hospital days for the class of drugs diabetes,

 

      asthma and gastric-acid disorder together, ER

 

      visits grew by 17 percent and hospital days by 10

 

      percent when co-pays doubled.  The authors

 

      acknowledge that these results are "not definitive"

 

      for reasons of data limitations.

 

                As a result, we are unable to quantify any

 

      effects on public health because of the nature of

 

      the limitations to the data.

 

                Let me offer a summary of what we know

 

      about the response to a price increase.  I have

 

      mentioned that an analysis would have, really,

 

      three parts.  With respect to the MDIs sold to a

 

      price-sensitive population, MEPS suggests that

 

      there are 2.8 million MDI albuterol prescriptions

 

                                                                73

 

      going to the uninsured patients with incomes of

 

      less than 400 percent of the poverty line who are

 

      not Medicare eligible and under age 65.

 

                If one takes, instead, data from the

 

      National Health Interview survey and combines that

 

      with data on the distribution of MDIs as described

 

      in the proposal, one ends up with a larger number

 

      of MDIs that would be used by the price-sensitive

 

      population.

 

                With respect to the price increase, we

 

      really have two estimates.  One is 120 percent

 

      increase.  That is from the IMS National

 

      Prescription Audit reflecting average prices for

 

      all payer types including those that are insured.

 

      We also have the 180 percent which reflects the

 

      Internet information.

 

                A key question pertaining to the analysis

 

      is the estimated elasticity, or the nature of the

 

      consumer response.  JAMA, as I mentioned, reports

 

      two numbers that may be plausible.  I think the

 

      0.15 is one that we focus on.  That reflects their

 

      estimate of the response to increases in co-pay for

 

                                                                74

 

      drugs with no OTC substitutes.  I think that is

 

      also consistent with other economics literature.

 

                The next question pertains to the

 

      interpretation of these.  The JAMA paper really

 

      focuses on consumer response for insured patients

 

      to higher co-pays.  They report an average co-pay

 

      of a little bit more than $12.  So that co-pay and

 

      the increase are roughly the same order of

 

      magnitude as the price and the price increase that

 

      one would anticipate for uninsured patients.

 

                So, if one applies that increase in price

 

      implicit in both the IMS data and in the Internet

 

      data and the consumer response implicit in the JAMA

 

      paper to the MDIs sold in the price-sensitive

 

      population, then it is reasonable to infer a

 

      quantity response among the uninsured population in

 

      the high hundreds of thousands.  It is very

 

      difficult to be more precise.  This is a daunting

 

      exercise with data that are imperfect, as we have

 

      acknowledged.  But the numbers that we have

 

      presented in particular are 0.4 million to 1

 

      million.  These are clearly approximate.

 

                                                                75

 

                Let me offer some empirical caveats.  I

 

      have neglected the response of insured patients to

 

      any increases in co-pays.  The JAMA paper measured

 

      these and we know that the co-pays for branded

 

      products are much higher than co-pays for generics.

 

      But this delisting of albuterols would have no

 

      direct effect on the co-pays.  The co-pays may

 

      change only in response to the changes of the

 

      insurance companies.  We, therefore, believe these

 

      are too uncertain for us to quantify at this time.

 

                Let me reiterate that the estimates of the

 

      price-sensitive population of the price increase

 

      and the consumer response, or the elasticity, are

 

      all relatively uncertain.

 

                There is another caveat with respect to

 

      the interpretation of these estimates.

 

      GlaxoSmithKline wrote to FDA on May 3 of 2004

 

      stating that 2 million complementary samples of

 

      Ventolin would be made available each year to

 

      physicians who may choose to reserve these inhalers

 

      for their lower-income patients.

 

                We are unable to assess quantitatively

 

                                                                76

 

      what this might do for any reductions in

 

      utilization because of the uncertainty associated

 

      with how they might actually be distributed in

 

      physicians' offices.  The GSK letter also said that

 

      it would freeze wholesale acquisition costs or

 

      prices thereby suggesting that the eventual HFA

 

      prices at the retail level would also be relatively

 

      constant.  As I have mentioned, that is an

 

      assumption that we maintain.

 

                The giveaway, in general, may

 

      significantly offset the loss of canisters provided

 

      it is well targeted to the most price-sensitive

 

      patients.

 

                Thank you for the opportunity to talk.  I

 

      would be happy to take questions.

 

                DR. CHINCHILLI:  Thank you, Dr. Lutter.

 

      Are there any questions from the committee?  Dr.

 

      Schatz?

 

              Questions from the Committee to the Speakers

 

                DR. SCHATZ:  My question is the

 

      relationship between elasticity and

 

      over-the-counter substitutes.  I gather that, with

 

                                                                77

 

      more over-the-counter substitutes, then elasticity

 

      is theoretically increased?

 

                DR. LUTTER:  Yes.

 

                DR. SCHATZ:  Then I would submit that

 

      there may be an over-the-counter substitute which

 

      is Primotine so that I think that, in

 

      consideration, one might have the higher elasticity

 

      and that patients doing that might be not as well

 

      served.

 

                DR. LUTTER:  Lacking your medical

 

      expertise, I will leave the judgment and the

 

      discussion about the substitutability of the OTC to

 

      you.  Let me simply say that the availability of

 

      OTC substitutes would affect the response in that

 

      way.

 

                DR. SCHATZ:  And it could make the higher

 

      value that they found more relevant than the lower

 

      value potentially.

 

                DR. LUTTER:  Yes.

 

                DR. CHINCHILLI:  Dr. Martinez?

 

                DR. MARTINEZ:  Certainly with the caveat

 

      which we may discuss later, but Primotine is not

 

                                                                78

 

      albuterol and, thus, a potential consequence that

 

      has not been thought of is that individuals who

 

      cannot afford albuterol anymore will start using

 

      over-the-counter Primotine which is associated with

 

      a completely different set of side effects which

 

      need to be seriously considered.

 

                DR. CHINCHILLI:  Ms. Schell, you had a

 

      question?

 

                MS. SCHELL:  Yes, thank you.  I just have

 

      a question about the shift of production of the CFC

 

      to the United States from the Netherlands in 2005.

 

      Do you project an increase in the CFC MDIs' cost

 

      with that shift of production coming to the U.S.?

 

                DR. LUTTER:  That is not something we have

 

      taken into account in the analysis.  We have no

 

      information on which to assess that question.

 

                MS. SCHELL:  Thank you.

 

                DR. CHINCHILLI:  Do any of the FDA

 

      representatives want to respond to that or the

 

      previous question?

 

                DR. MEYER:  I think, as far as that

 

      question--I don't think we have data that could say

 

                                                                79

 

      one way or the other.  Not the least of the

 

      considerations there is how much in the price does

 

      the actual cost of CFCs play, and I don't think we

 

      know that.

 

                As far as the earlier question and point,

 

      I think it is something we can certainly consider

 

      as we consider all the input from today.

 

                DR. CHINCHILLI:  Dr. Swenson, you had a

 

      question?

 

                DR. SWENSON:  Yes.  Regarding that JAMA

 

      article, did you pursue at all the cost

 

      implications of this greater ER and hospitalization

 

      rate that might arise from some of these shifts

 

      that you have postulated?

 

                DR. LUTTER:  No, largely because of the

 

      uncertainty in quantifying those increases.  As I

 

      mentioned, there were three categories of

 

      therapeutic classes that they grouped together only

 

      one of which was asthma.  Albuterol is only one

 

      treatment for asthma and, therefore, we thought

 

      that inferring--that the judgment of the

 

      applicability of those estimates to this delisting

 

                                                                80

 

      appeared to--is that we have no basis to accept

 

      those estimates to predict quantitative reductions,

 

      quantifiable reductions, in the ER visits or days

 

      in the hospital.  So, therefore, we don't really

 

      want to estimate either the cost of reductions or

 

      increases associated with those either.

 

                DR. CHINCHILLI:  Dr. Moss?

 

                DR. MOSS:  I work at Grady Memorial

 

      Hospital which serves an indigent-care patient

 

      population.  About 40 percent of the patients there

 

      are self-pay which means they don't have insurance.

 

      It is nice way of saying that.  One of the big

 

      problems in the hospital is the in-hospital

 

      pharmacy costs.  Do you have any information or is

 

      there a way to figure out how the changing cost of

 

      inhalers would affect operating at a hospital that

 

      serves indigent-care patients or is there a way to

 

      figure that out?

 

                DR. LUTTER:  There probably is a way to

 

      figure it out.  It is not something we have done.

 

                DR. CHINCHILLI:  Dr. Kercsmar?

 

                DR. KERCSMAR:  The transition to HFA

 

                                                                81

 

      inhalers has been made in a number of other

 

      developed and industrialized countries.  Are there

 

      any data that are comparable to that that has been

 

      published in the JAMA article?  You referenced that

 

      might give other insight into the elasticity

 

      problem, changes in morbidity, lack of prescription

 

      refills or, because of the difference in economic

 

      structure and drug reimbursement in these

 

      countries, are there no data available?  Are there

 

      lessons to be learned from countries that have

 

      already made the transition?

 

                DR. LUTTER:  It is a good question.  We

 

      thought of that.  Other countries lack the

 

      uninsured population that exists in the United

 

      States and generally control prices.  In

 

      particular, the price discrepancy that I have

 

      described here is unusual if not unique.

 

                DR. CHINCHILLI:  Any other questions by

 

      the committee members for Dr. Lutter?

 

                MR. MITCHELL:  Just before the break there

 

      is something I would like to say.

 

                DR. CHINCHILLI:  Yes; please go ahead.

 

                                                                82

 

                MR. MITCHELL:  This is addressed to the

 

      people who are watching this procedure through the

 

      webcast.  The proposed rule that we have been

 

      discussing is available on FDA's website if you go

 

      to www.fda.gov.  In the middle column, you should

 

      see FDA advanced display.  If you click on that,

 

      you should be able to see another link which goes

 

      to advanced publication display.  Click on that and

 

      you should see something about a special filing,

 

      publishing, on June 16, 2004.  That should get you

 

      to the Notice of Proposed Rulemaking.

 

                Thank you, Mr. Chairman.

 

                DR. CHINCHILLI:  Thank you, Dr. Mitchell.

 

      Yes; Ms. Schell?

 

                MS. SCHELL:  I am not sure who to direct

 

      this question to, but I have a question.  Several

 

      of you talked about what the ozone depletion does

 

      in cataracts, skin cancer and that, but no one has

 

      mentioned how it affects asthmatics of COPD

 

      patients, the depletion of the ozone layer and how

 

      that would increase, if we didn't do something now,

 

      how the ozone depletion would affect asthmatics in

 

                                                                83

 

      the future.  Would we be causing more asthmatics to

 

      have problems with their breathing?

 

                Thank you.

 

                DR. MEYER:  I will try to answer that.  I

 

      think it is unclear to us that asthma or COPD

 

      patients would be differentially affected in terms

 

      of the environmental consequences of ozone

 

      depletion.  You were not asking this, but, for the

 

      public, I think it is hard for them to understand

 

      that ozone in the lower regions of the atmosphere

 

      is bad for asthmatics, particularly, and probably

 

      for COPD as well.  But ozone in the stratosphere

 

      probably has no bearing on the development of

 

      asthma and COPD that we know of.

 

                So we would assume that the consequences

 

      to the asthmatic and COPD population would be the

 

      same as to consequences to other populations.  One

 

      could perhaps try to parse that out more closely in

 

      that it is potential that inhaled corticosteroids,

 

      for instance, may somewhat increase the

 

      predisposition to cataracts.  Whether that would be

 

      even more the case in the circumstances of a

 

                                                                84

 

      thinned ozone layer, who knows.  But, again, we

 

      have no basis at this point to believe that there

 

      would be a differential effect on those patients.

 

                DR. CHINCHILLI:  Any other questions from

 

      committee members for our FDA representatives?

 

      Yes?

 

                DR. MEYER:  I just wanted to make the

 

      point--I realize that the people sitting around

 

      this table probably are fairly well versed in this

 

      but, for the purposes of the public, I realize that

 

      we didn't really sort of step back and make this

 

      point.  But albuterol has really become a prime

 

      drug for both the treatment of asthma, in

 

      particular, but also for COPD in a way that, even

 

      when we began the advanced notice of proposed

 

      making in '96, I don't think we have fully

 

      anticipated.

 

                It is now clear that approximately 50

 

      million or more canisters of albuterol are

 

      necessary to treat patients with asthma and COPD in

 

      the United States.  It is, again, by far and away

 

      the bronchodilator or short-acting reliever of

 

                                                                85

 

      choice in patients with asthma and COPD.

 

                Again, I think the people around the table

 

      know this but, for the matter of the public record,

 

      I just wanted to get on the table the kind of

 

      numbers we are talking about.  This is a very

 

      important drug that is sold widely and is really

 

      critical in the asthma armamentarium and very

 

      important in the COPD armamentarium as well.

 

                DR. CHINCHILLI:  Thank you, Dr. Meyer.

 

      Dr. Martinez?

 

                DR. MARTINEZ:  I have one question

 

      regarding worldwide distribution of sales.  What is

 

      the situation in the underdeveloped world?  Which

 

      are the products that are sold there and what are

 

      the projected consequences of this regulation in

 

      that particular market?

 

                DR. MEYER:  From the FDA perspective, I

 

      don't think we have a lot of information on that.

 

      I also am involved in the Montreal Protocol on a

 

      working group on aerosols, medical aerosols.  I can

 

      say that the United States actually exports

 

      relatively few of its MDIs as opposed to the EU

 

                                                                86

 

      where much of their production is exported.

 

                So most of what we are talking about here

 

      is for domestic consumption and will not really

 

      have much bearing on the rest of the world.  I

 

      would parenthetically note that there is a lot of

 

      attention paid in the Montreal Protocol about how

 

      this phase-out in the developed world will affect

 

      that in the developing world because it is a very

 

      important issue.

 

                Unfortunately, in much of the developing

 

      world, the use of MDIs is not very common because

 

      they are--although they are cheap per dose, to

 

      actually buy one requires you to buy a certain

 

      number of doses as opposed to oral medications

 

      which may be more expensive per dose but cheaper

 

      where you can just buy a few.

 

                So there is probably undertreatment in the

 

      developing world in general and specifically there

 

      is not a lot of use of MDIs relative to the

 

      developed world.

 

                DR. CHINCHILLI:  Before we proceed with

 

      other questions, I would like to welcome Dr. Reiss

 

                                                                87

 

      to the committee.  Would you turn on your

 

      microphone and introduce yourself to everyone?

 

                DR. REISS:  Sure.  I apologize for being

 

      late this morning.  I am Ted Reiss from Merck

 

      Research Labs.  I am the industry non-voting

 

      representative on the committee.

 

                DR. CHINCHILLI:  Thank you.  Any other

 

      questions?  Yes; Dr. Swenson?

 

                DR. SWENSON:  Dr. Meyer, a couple

 

      questions.  I didn't see anywhere in the data,

 

      either in the background information, if you could

 

      go back to the initial signing of the protocol.  At

 

      that point, how much CFC was being produced and

 

      now, of that amount, what does the present use of

 

      CFC in albuterol represent in a percentage term or

 

      absolute amount?

 

                DR. MEYER:  I am sorry that I don't

 

      actually have those particular figures available.

 

      I can say that the use of CFCs for MDIs when the

 

      protocol was signed was a relatively small

 

      proportion of the CFC use because CFCs were then

 

      used in refrigerators, auto air conditioners, home

 

                                                                88

 

      air conditioners, foams and so on.

 

                Now that the provisions of the Copenhagen

 

      Amendments went into place, the use of CFCs for

 

      MDIs in the developed world is the large majority

 

      of these CFCs but it is still a small fraction

 

      compared to what was the total in 1987.

 

                Albuterol in both the United States and in

 

      the rest of the world has been a prominent use of

 

      CFCs.  As I mentioned, for the United States, it

 

      amounted to about half, or does amount to about

 

      half, of our essential-use denomination.  So I am

 

      not giving you specific numbers, but I hope I am

 

      sort of giving you a qualitative feel.

 

                DR. SWENSON:  Okay.  The next question I

 

      have then is, on Slide 24 or one of the similar

 

      slides that you had in your talk, was the projected

 

      return, or this idea of a projected return, of

 

      normal stratospheric ozone levels by mid-century

 

      based on the present use right now which includes

 

      our use of CFCs or was that based on complete

 

      elimination of CFCs?

 

                DR. MEYER:  Those projections, and just to

 

                                                                89

 

      be clear, they are actually projecting the recovery

 

      to early 1980s levels which was still not normal

 

      but a recovery nonetheless, are based on the

 

      successful conduct of the Montreal Protocol.  So it

 

      is based on the Montreal Protocol as currently

 

      amended being successfully carried out into the

 

      future.

 

                DR. CHINCHILLI:  Ms. Schell?

 

                MS. SCHELL:  I am sorry.  I would like one

 

      more question on the 50 million uses of Ventolin or

 

      albuterol.  Have you looked at the overuse of

 

      albuterol and the underuse of the

 

      anti-inflammatory?  Is there any look at overuse?

 

      As we know, asthmatics, a lot of the time, don't

 

      have the proper education in the use of the

 

      anti-inflammatory so they overuse their albuterol.

 

      Are there any numbers reflecting that?

 

                Thank you.

 

                DR. MEYER:  We do not have such numbers.

 

      It is certainly something that we considered.  As

 

      Dr. Lutter said, there are a lot of things we would

 

      wish to consider in an ideal analysis.  One of the

 

                                                                90

 

      complications of projecting a public-health

 

      consequence of some drop in the number of albuterol

 

      MDIs distributed or used relates to these

 

      questions, relates to the possibility that when

 

      beta-adrenergic bronchodilators are overused that

 

      that might, itself, have detrimental effects.

 

                But these things, although clearly we

 

      think about them, are not something we can

 

      reasonably quantitate.  So we have not.

 

                DR. CHINCHILLI:  Any other questions from

 

      the committee?  If not, I want to thank the FDA for

 

      enlightening us on these issues.  We are scheduled

 

      for a break at 10:00.  We are about eight minutes

 

      before that, so we will take the break early.  But

 

      I would like to reconvene at 10:10.

 

                Thank you.

 

                (Break.)

 

                DR. CHINCHILLI:  I do have one

 

      announcement and that is if you have a cell phone

 

      and it must be on, it would be preferable if you

 

      put it on vibrating mode and then, if it does go

 

      off, that you take your call outside the room. 

 

                                                                91

 

      Thank you.

 

                Before we go on to the open public

 

      hearing, the first session that we will have this

 

      morning, I just want to make sure that the

 

      committee members don't have any other questions

 

      for the FDA representatives.  Are there any other

 

      questions from the committee?  Any final comments

 

      from the FDA?

 

                If not, then we are going to move into the

 

      open public hearing.

 

                    Open Public Hearing (Session 1)

 

                DR. CHINCHILLI:  One other announcement I

 

      am supposed to make.  Both the Food and Drug

 

      Administration and the public believe in a

 

      transparent process for information gathering and

 

      decision making.  To ensure such transparency at

 

      the open public hearing session of the advisory

 

      committee meeting, the FDA believes that it is

 

      important to understand the context of an

 

      individual's presentation.

 

                For this reason, the FDA encourages you,

 

      the open public hearing speaker, at the beginning

 

                                                                92

 

      of your written or oral statement, to advise the

 

      committee of any financial relationship that you

 

      may have with any company or any group that is

 

      likely to be impacted by the topic of this meeting.

 

                For example, the financial information may

 

      include a company's or a group's payment of your

 

      travel, lodging or other expenses in connection

 

      with your attendance at the meeting.  Likewise, the

 

      FDA encourages you, at the beginning of your

 

      statement, to advise the committee if you do not

 

      have any such financial relationships.

 

                If you choose not to address this issue of

 

      financial relationships at the beginning of your

 

      statement, it will not preclude you from speaking.

 

                So that is important for our open public

 

      hearing speakers to recognize that and to make

 

      acknowledgments.  I probably will repeat this

 

      statement when we start the afternoon session as

 

      well.

 

                We are ready for our first speaker during

 

      the open public hearing.  Please be sure to

 

      introduce yourself and pay attention to the

 

                                                                93

 

      statement I just made.

 

                MS. WEXLER:  Good morning.  I am Pamela

 

      Wexler.  Since 1997, I have served as attorney and

 

      advisor to the U.S. Stakeholders Group on MDI

 

      transition.  I have no financial interest in any of

 

      the companies or participants today.

 

                I would like to start by telling you a

 

      little bit about the U.S. Stakeholders Group.  It

 

      is a consortium of nine leading patient and medical

 

      professional organizations.  Members of the

 

      organizations include patients with asthma, chronic

 

      obstructive pulmonary disease and other respiratory

 

      diseases.  Collectively, the member organizations

 

      represent and reach 25 million Americans who suffer

 

      from asthma and other respiratory diseases and they

 

      include organizations that educate and advocate for

 

      individual patients and their families through

 

      local chapters.

 

                Members of the Stakeholders Group also

 

      include physicians, respiratory therapists and

 

      other healthcare professionals who specialize in

 

      respiratory care and they are recognized leaders

 

                                                                94

 

      among the healthcare community.  The stakeholders,

 

      as a group, and its member organizations

 

      individually collaborate with various other

 

      interested organizations in the U.S. and around the

 

      world.

 

                In the eight years since the Stakeholders

 

      Group has acted formally, neither its membership

 

      nor its procedures have changed.  The American Lung

 

      Association convenes the U.S. Stakeholders Group.

 

      The member organizations elect representatives to

 

      the stakeholders process and these individuals

 

      meet, in person, once or twice a year and

 

      communicate regularly.

 

                Oftentimes, the leadership of these

 

      organizations attends stakeholder meetings and

 

      participates in the deliberations.  Other times,

 

      the government and the private sector are invited

 

      to attend as well and make presentations.  Any

 

      action taken under the name of the stakeholders is

 

      approved by each member organization.

 

                Now, I would like to turn to our petition.

 

      Eighteen months ago, we petitioned FDA to consider

 

                                                                95

 

      albuterol essentiality.  The petition was not

 

      precipitous.  It, in fact, was requesting the

 

      agency merely consider essentiality.  It was FDA,

 

      itself, in a rulemaking process that started in

 

      1997 and lasted five years that set up these

 

      essentiality criteria, the conditions under which

 

      any drug substance would be delisted and no further

 

      CFCs would be available.

 

                The stakeholders petition asserted that

 

      the criteria had been met or, with the case of

 

      manufacturing capacity, that the criteria could be

 

      met or that information could be ascertained and,

 

      hence, it was time for FDA to consider removing the

 

      essential-use designation.

 

                Now, there are a number of reasons why the

 

      stakeholders petitioned FDA.  I will just take a

 

      moment to touch on them.  First and foremost is the

 

      environmental imperative.  I won't spend too much

 

      time on this because I think that the importance of

 

      repairing the ozone layer is well established, both

 

      by the Montreal Protocol and the U.S. Clean Air Act

 

      on which, by the way, the U.S. has been a leader

 

                                                                96

 

      since the beginning on the international process.

 

      FDA, in its July, 2002 Final Rule establishing the

 

      essentiality criteria actually offered a very

 

      concise and clear explanation of why every use of

 

      CFCs must be eliminated, even seemingly small

 

      amounts like those used in MDIs.

 

                I won't spend too much time on the second

 

      sub-bullet either because a physician from one of

 

      our member organizations in the next session, later

 

      this afternoon, will present more on the

 

      opportunity to improve disease management.  But let

 

      me just say that, from its inception, the

 

      stakeholders position on the potential of

 

      transition has not changed and that is that we

 

      understand the potential of a switch in medication

 

      and we have worked, and we hope to continue to

 

      work, to ensure that that experience provides an

 

      opportunity to improve patient care.

 

                On the third and the last, and probably

 

      the most pressing, issue for patients and

 

      physicians is the issue of CFC supply and how it

 

      might affect the availability of medications.  As I

 

                                                                97

 

      am sure you will hear more about today, the future

 

      of CFCs to make MDIs is uncertain and fundamentally

 

      the stakeholders want FDA to sufficiently plan for

 

      that and for CFC-free medications to be available

 

      and widely accepted before CFC supply can have any

 

      impact on product availability or price.

 

                Since the petition was filed, in the

 

      eighteen months since the stakeholders filed the

 

      petition to consider albuterol essentiality, a lot

 

      has changed and we have learned a lot more.  As to

 

      supply, anyone who follows this knows that, in the

 

      past three to five years, there has been a lot of

 

      new and often conflicting information about where

 

      PhRMA-grade CFCs were going to come from after

 

      December 31, 2005.

 

                Remember, that is an issue simply for the

 

      U.S. market because, for the most part, developed

 

      countries will not need these chemicals after that

 

      date.  They are on pace to phase out the use of

 

      CFCs in MDIs.

 

                The stakeholders have never had full

 

      information on the future of CFC supply.  We heard

 

                                                                98

 

      originally, maybe two years ago, there were going

 

      to be two plans, one in Europe and one here.  They

 

      we heard that that wasn't going to happen.  Then

 

      the issue of certification was raised, that plants

 

      had to be certified, the CFCs produced had to be

 

      certified, and that the production that would

 

      replace the production that is going to be lost in

 

      Europe would be a different kind of production and

 

      that different specifications would be required.

 

                We heard, now, recently, despite a letter

 

      from Honeywell indicating its stated intent to

 

      supply CFCs at a plant in Baton Rouge, Louisiana,

 

      that we still had questions about certification as

 

      that was not mentioned in the letter and we have

 

      never heard anything further about FDA on what,

 

      exactly, that requires.

 

                So the stakeholders, themselves, have

 

      limited information on which they could base a

 

      conclusion that the CFC supply would be without

 

      problems.  Recently, a non-governmental

 

      organization, NRDC, wrote the EPA suggesting that

 

      it would be illegal to produce CFCs in Baton Rouge.

 

                                                                99

 

      So, again, we are faced with not a lot of clear

 

      information on how we will go forward.

 

                As to the second sub-bullet, even if the

 

      Baton Rouge plant is not a problem, we certainly

 

      see an increase in pressure on the part of the

 

      international community to limit future supply of

 

      CFCs especially where there are alternatives as in

 

      the case of albuterol.  We heard recently that the

 

      U.S. request that was recently put into the parties

 

      was approved but with the strong suggestion that

 

      the U.S. come back to the parties after this

 

      rulemaking was complete since it wasn't clear that

 

      those quantities would be needed.

 

                So it is obvious that the parties are

 

      signalling the intent to stop authorizing new CFC

 

      production for MDIs, again, in the case of a drug

 

      like albuterol where there are safe alternatives.

 

                Also, since the petition was filed, we

 

      have, in the FDA docket, an independent analysis

 

      conducted by National Economic Research Associates,

 

      NERA, that provided us a much better picture of the

 

      albuterol market.  I expect that we will hear more

 

                                                               100

 

      about the NERA analysis this afternoon, but it gave

 

      us a very good picture of how the market is

 

      supplied, how patients who rely on albuterol pay

 

      for their drugs.

 

                It estimates the price and what the market

 

      might look like once HFA alternatives are

 

      introduced.  More importantly, NERA projects how

 

      the increased costs might be distributed and

 

      allocated among the different classes of patients,

 

      managed care and other payers including Medicare

 

      and Medicaid.

 

                Now, you know, the stakeholders are

 

      medical and patient advocates, medical

 

      professionals and patient advocates.  We are not

 

      economists.  So we aren't here to speak to the

 

      specific numbers in the NEAR report but we do

 

      believe that the general thrust of the report

 

      comports with what we have always believed about

 

      the albuterol market and our understanding of how

 

      increases, not just in medications but in all sorts

 

      of other medical procedures and services rise and

 

      are absorbed in the healthcare system.

 

                                                               101

 

                Now, there is no mistake about the need to

 

      ensure patient access to medication.  In our

 

      petition to FDA, we were clear that FDA needed to

 

      take into account price and how it would affect

 

      patients and their ability to obtain medication and

 

      comply with their treatment regimens.  But we think

 

      that, between the manufacturers, the stakeholders

 

      and FDA, collective, we can adequately protect the

 

      potentially at-risk subgroups and we can do it in a

 

      variety of ways.

 

                On the part of the manufacturers, we have

 

      one submission already in the docket from an HFA

 

      manufacturer outlining what it intends to do.  We

 

      would hope that we would see similar commitments

 

      from other manufacturers as we move forward about

 

      increasing the number of samples and enhancing

 

      patient-assistance programs.

 

                On the part of the stakeholders, our

 

      member organizations are committed to working with

 

      the agency and the manufacturers to develop an

 

      educational strategy for communicating the

 

      availability of free and discounted albuterol.  We

 

                                                               102

 

      can work with our member organizations and our

 

      network to deploy these messages in advance of

 

      transition to patients, to specialty, general

 

      physicians and the rest of the healthcare

 

      community.

 

                As for FDA, we think that there also might

 

      be mechanisms that the agency can consider to

 

      protect, again, these potentially at-risk

 

      populations.  One thing we have discussed within

 

      stakeholder meetings is for FDA to monitor the

 

      patient compliance or access to HFA albuterol and

 

      reserve the right to allow a certain number of CFC

 

      MDIs to be sold in the case of a real emergency so,

 

      if you will, a phase-down process that allows the

 

      potential--and that is the potential in both CFC

 

      supply and manufacturing capacity to not be gone

 

      before we are out of transition, so a phase-down

 

      period that protects that at-risk population.

 

                I think that if FDA acts in a relevant

 

      timeframe, there would still be enough stockpile to

 

      be able to incorporate such a mechanism.

 

                Last, I would like to turn to the timing

 

                                                               103

 

      of transition.  There has been a lot of talk about

 

      when the right time is.  Now, it is no secret that

 

      the stakeholders have long supported December 31,

 

      2005 as the effective date for removing CFC

 

      albuterol from sale in the U.S.  As early as 1996,

 

      in fact, before we had ever heard the word "TEFA"

 

      or "WEERT," we embraced the idea of a target date.

 

                We embraced the eventuality that these

 

      chemicals as slated for elimination.  We understood

 

      that it was useful to have a target date so that

 

      manufacturing capacity could be put into place.

 

      That idea of an aim, a target, a goal, has proven

 

      successful as is evidenced by the fact that the

 

      rest of the world or the rest of the developed

 

      countries also adopted that date and or on pace to

 

      meet it.

 

                We saw transition as an opportunity to

 

      educate physicians and patients about the learning

 

      that has been done, especially in the last decade,

 

      regarding asthma treatment and management.

 

                But, in 1996, we saw December 2005 as a

 

      goal, not an imperative.  Eight years later, we now

 

                                                               104

 

      know that WEERT will close.  We know there are

 

      additional uncertainties regarding the Baton Rouge

 

      facility.  We know that there are two alternatives

 

      ready to go and a third on the way.  Given that,

 

      December 31, 2005 makes a lot of sense.

 

                Again, I just want to go back to

 

      mechanisms for actually proceeding through

 

      transition.  Ending at December 31 is sensible and

 

      it is achievable and, most importantly, it is

 

      near-term enough that any problems with HFA

 

      production, any problems with patient access, any

 

      problems with affordability, compliance, any

 

      unforeseen consequences, can be discovered and

 

      addressed before CFCs are unavailable and before

 

      the capacity to produce additional CFC products is

 

      gone.

 

                Thanks very much.

 

                DR. CHINCHILLI:  Thank you very much.

 

                We will move on now to our second speaker.

 

                DR. JONES:  Good morning.  My name is

 

      Elaine Jones and I am Vice President of U.S.

 

      Regulatory Affairs at GlaxoSmithKline.  On behalf

 

                                                               105

 

      of GlaxoSmithKline, I would like to thank the

 

      advisory committee and the agency for opportunity

 

      to present our commitment to the transition from

 

      albuterol CFC-free metered-dose inhalers, or MDIs,

 

      which are ozone-depleting to albuterol HFA MDIs,

 

      which are non-ozone-depleting.

 

                Principally, during this presentation, I

 

      will address the two questions that have been posed

 

      to us by the agency that relate to the FDA's

 

      criteria for transition.

 

                The first question concerns our

 

      manufacturing capacity for Ventolin HFA and the

 

      second, what GSK programs are, or will be put in

 

      place to help ensure that patients are adequately

 

      served during the transition from albuterol CFC to

 

      albuterol HFA and thereafter.

 

                To set the stage for discussion of the two

 

      principle questions, I would like to review the

 

      timing of Ventolin HFA development in relation to

 

      implementation of the Montreal Protocol.

 

      Development of Ventolin HFA started before the

 

      Montreal Protocol was ratified and resulted in

 

                                                               106

 

      submission of a new drug application in 1998.

 

      Filing of this NDA was the result of over ten years

 

      of research and development including a technically

 

      challenging reformulation effort under

 

      comprehensive clinical program.

 

                After gaining FDA approval, GSK launched

 

      Ventolin HFA in 2002 and stopped the sale of

 

      Ventolin CFC.  Currently, GSK sells Ventolin HFA in

 

      165 countries around the world which has resulted

 

      in over 20 million patient years of experience.

 

      Also, in 2002, FDA published its final rule

 

      outlining the criteria for transition from CFC

 

      MDIs, which was the culmination of a lengthy

 

      process that took five years to complete.

 

                Quoted on this slide is one of the

 

      criteria for transition from the 2002 Final Rule.

 

      FDA has asked us, as one of the manufacturers of

 

      the replacement products for albuterol CFC MDIs to

 

      address this criterion which relates to the issue

 

      of adequate supply and production capacity.

 

      Specifically, the question is, can GSK, in

 

      conjunction with other manufacturers of the

 

                                                               107

 

      replacement albuterol product, manufacture

 

      sufficient quantities to satisfy patient demand

 

      after the CFC products are no longer available.

 

                To help answer this question, here is a

 

      graphical representation of GSK's manufacturing

 

      capacity over time in relation to the overall

 

      albuterol market.  Other manufacturers can be

 

      expected to contribute to the supply as well.  At

 

      present, patient need for albuterol MDIs is about

 

      50 million per year, as shown by the yellow shading

 

      in this graph.  This demand has remained fairly

 

      constant over the past five years and is expected

 

      to remain constant into the future.

 

                The blue shaded portions of the graph

 

      represent two distinct components of GSK's ability

 

      GSK's ability to contribute to meeting this demand

 

      with CFC-free MDIs.  The darker shaded blue area

 

      reflects currently installed capacity and the

 

      lighter shaded blue area reflects expansion

 

      capacity.  The sum total of both components is

 

      about 30 million MDIs per year, or about 60 percent

 

      of the expected market.

 

                                                               108

 

                Now, I would like to discuss in detail our

 

      current capacity.  GSK manufacturers Ventolin HFA

 

      at a facility in Zebulon, North Carolina, which has

 

      a long history of manufacturing MDIs including the

 

      now discontinued Ventolin CFC.  At this facility,

 

      we already have installed the capacity to

 

      manufacture 15 million Ventolin HFA MDIs.  At

 

      present, since transition has yet to take place, we

 

      are utilizing only 2 percent of our installed

 

      capacity.

 

                Production of up to 5 million MDIs could

 

      be achieved immediately and this could be

 

      progressively increased to the full 15 million MDIs

 

      within six to twelve months.  To achieve this

 

      capacity is a relatively straightforward process.

 

      We would need to hire additional staff and

 

      reconfigure existing space.

 

                As illustrated on the graph I presented

 

      earlier, GSK is prepared to increase production

 

      capacity by an additional 15 to 18 million MDIs.

 

      This would entail significant capital investigation

 

      on the part of GSK, would take approximately twelve

 

                                                               109

 

      to eighteen months to complete and would require

 

      the installation of additional manufacturing

 

      equipment and securing of MDI components.

 

                This could be undertaken simultaneously

 

      with a previous increase in production.  This

 

      expansion, in addition to our current capacity,

 

      would deliver a total of approximately 30 million

 

      MDIs.

 

                I would now like to address the second

 

      question posed to us by the agency which concerns

 

      another one of the criteria in the 2002 Final Rule

 

      on Essential Use Determinations and is reflected on

 

      this slide.  The issue is whether a high-priced,

 

      non-ODS, product is effectively unavailable to a

 

      portion of the patient population because they

 

      cannot afford to buy the product.

 

                Payers, and the healthcare system overall,

 

      may experience higher costs as the market

 

      transitions to CFC-free albuterol.  But the

 

      relevant question under FDA's 2002 Final Rule is

 

      how individual patients will be impacted by this

 

      transition, specifically whether they will have

 

                                                               110

 

      adequate access to CFC-free formulations of

 

      albuterol.

 

                The larger policy questions regarding a

 

      balancing of societal cost against environmental

 

      benefits have already been resolved by the Montreal

 

      Protocol.

 

                In order to assess the economic impacts of

 

      an albuterol transition, GSK commissioned a study

 

      by the National Economic Research Associates.  The

 

      analysis proceeded on the basis of data collected

 

      from a variety of sources as shown on this slide.

 

      Although the economic report examined impacts on

 

      payers as well as patients, our focus today is on

 

      the impact a transition will have on the access to

 

      albuterol HFA MDIs for individual patients.

 

                To understand the impact on patients, one

 

      must appreciate that albuterol is dispensed to

 

      patients in different settings including retail

 

      pharmacies, hospital pharmacies, clinics and

 

      federal healthcare facilities.  As represented by

 

      the large green slices of pie chart, 84 percent of

 

      dispensing takes place at retail pharmacies.  The

 

                                                               111

 

      remaining 16 percent takes place in other settings;

 

      for example, a Veterans Administration Hospital

 

      where financial impacts on patients, of changes in

 

      drug prices, are likely to be quite limited.

 

                The pie chart on the right reflects a

 

      further breakdown of the retail-pharmacy segment.

 

      Within the retail portion, 72 percent of MDIs are

 

      covered by private drug insurance and 15 percent

 

      are covered by Medicaid.  About 13 percent of

 

      albuterol MDIs dispensed by retail pharmacies go to

 

      patients who pay cash.  GSK recognizes that it is

 

      within this group of patients that the greatest

 

      concern exists regarding access to albuterol MDIs

 

      after a transition.

 

                As we consider the patients who pay cash

 

      for their prescriptions, it is important for us to

 

      emphasize our long-standing dedication to helping

 

      those in need obtain access to our medicines.  For

 

      over two decades, GSK and its Heritage Companies

 

      have been committed to helping patients without

 

      public or private drug insurance to get the

 

      medicines that they need.  To this end, we have had

 

                                                               112

 

      in place various patient assistant programs.

 

                I will now describe Bridges to Access, the

 

      GSK program which is directed at patients of all

 

      ages who require financial assistance.  For those

 

      who qualify, GSK offers its medicines, including

 

      Ventolin HFA, at no cost or at a minimal

 

      retail-pharmacy dispensing fee.

 

                Individuals with annual incomes up to

 

      $25,000 or families at or below 250 percent of the

 

      federal poverty level are eligible for Bridges to

 

      Access.  Patients who enroll can receive their

 

      medication the same day that it is prescribed.

 

      This program also includes a spend-down option that

 

      allows patients to deduct medical bills from their

 

      income for purposes of determining eligibility

 

      requirements.

 

                Patients are not required to be U.S.

 

      citizens to qualify for Bridges to Access.

 

      Patients who apply also receive assistance in

 

      finding additional healthcare programs for which

 

      they qualify such as Medicaid, AIDS drug-assistance

 

      programs, state children's health insurance and

 

                                                               113

 

      state elderly drug-assistance programs.

 

                In this visual illustration, we use the

 

      federal poverty level as a baseline to compare the

 

      income eligibility levels for Medicaid and Bridges

 

      to Access.  The yellow line represents the federal

 

      poverty level income for households of different

 

      sizes ranging from one to four members.  The blue

 

      lines represent the average income eligibility

 

      ceiling for Medicaid which is 135 percent of the

 

      federal poverty level.

 

                Each orange bar represents the maximum

 

      qualifying income under Bridges to Access for a

 

      household of that size.  This maximum qualifying

 

      income level is $25,000 for households with one

 

      individual or 250 percent of the federal poverty

 

      level for households with more than one individual.

 

                I might add that certain patients who do

 

      not meet   Medicaid's eligibility requirements

 

      despite meeting the income requirements could

 

      potentially qualify for Bridges to Access.  For

 

      lower-income patients who do not have public or

 

      private drug insurance, for whatever reason,

 

                                                               114

 

      Bridges to Access is, thus, a valuable resource.

 

                GSK's experience with Bridges to Access

 

      for Ventolin HFA from June 2003 to May 2004

 

      illustrates the program benefits for patients.  We

 

      have distributed nearly $3 million worth of product

 

      representing approximately 100,000 inhalers to

 

      nearly 14,000 patients.  During this period of

 

      time, the total amount of Ventolin HFA distributed

 

      was approximately 400,000 MDIs which means that one

 

      out of four Ventolin HFA MDIs went to a Bridges to

 

      Access patient.

 

                GSK has generated awareness of this

 

      program through various avenues including half a

 

      million letters sent to advocates at the launch of

 

      the program, training for healthcare providers and

 

      partnerships with public agencies and professional

 

      associations.  In addition, we maintain a public

 

      website with extensive information about our

 

      program including application forms.

 

                These activities represent some of the

 

      significant efforts GSK has made to raise awareness

 

      of the program and we look forward to continuing

 

                                                               115

 

      our outreach efforts.  We are committed to provide

 

      Ventolin HFA to all eligible patients in the event

 

      of an increased need at the time of transition.  In

 

      order to show more clearly the estimated financial

 

      impact of a transition to CFC-free albuterol on

 

      individuals, I would like to now illustrate how a

 

      lower-income patient might fare in a transition

 

      both with and without the benefit of Bridges to

 

      Access.

 

                Our hypothetical patient is an individual

 

      who makes less than $25,000 a year and, thus,

 

      qualifies for Bridges to Access and who also uses

 

      four albuterol inhalers.  To make this calculation,

 

      we compared the current average wholesale price of

 

      Ventolin HFA to the mean of the average wholesale

 

      prices for the three top selling generic albuterol

 

      inhalers.

 

                Average wholesale price, or AWP, is

 

      commonly used as a pricing reference point for

 

      distributors and payers in the healthcare system

 

      and is calculated and reported by commercial data

 

      vendors.  GSK does not set an AWP for its products

 

                                                               116

 

      or sell its products according to AWP and we

 

      recognize published AWPs are different from actual

 

      prices paid in the marketplace.

 

                Based on the AWP comparison, the current

 

      difference in price between Ventolin HFA and

 

      generic albuterol is $9.49.  Therefore, in our

 

      example, if the patient did not enroll in Bridges

 

      to Access, the extra cost per month would be $3.16

 

      or $37.96 a year.

 

                With assistance from Bridges to Access,

 

      the cost of Ventolin HFA would be limited to a

 

      one-time charge of $10.00 for the patient's first

 

      60-day retail pharmacy fill.  The patient would

 

      then experience no added cost for further

 

      prescription.  In fact, the medicine would be

 

      entirely free from that time forward.

 

                Keep in mind that this hypothetical

 

      patient, if not enrolled in Bridges to Access prior

 

      to the transition, would previously have been

 

      paying out of pocket for that generic albuterol.

 

                For seniors or disabled persons, in

 

      addition to Bridges to Access, GSK offers the

 

                                                               117

 

      saving programs, Orange Card and Together Rx to

 

      help make GSK medicines more affordable.  The GSK

 

      Orange Card was the first of its kind.  It is

 

      available for Medicare beneficiaries without any

 

      prescription-drug insurance and incomes of up to

 

      $30,000 for an individual and up to $40,000 for a

 

      married couple.

 

                Orange Card offers savings on GSK products

 

      including Ventolin HFA to eligible Medicare

 

      beneficiaries of up to 40 percent depending on a

 

      pharmacy's usual and customary price for the

 

      medicine.  The program, Together Rx,  is a

 

      multi-company savings program and, as such,

 

      provides access to a larger number of medicines.

 

      This program was modeled after the GSK Orange Card

 

      and has similar eligibility criteria.

 

                Although the arrival of a Medicare drug

 

      benefit in January 2006 should substantially lessen

 

      the need for assistance of this kind, GSK's

 

      commitment to helping patients access our medicines

 

      will remain.

 

                In addition, GSK has committed to provide

 

                                                               118

 

      at least 2 million professional samples of Ventolin

 

      HFA each year beginning a transition.  Although

 

      samples are distributed to physicians with no

 

      conditions attached, we understand, anecdotally,

 

      that many physicians do take medication-access

 

      considerations into account in allocating samples

 

      among their patients.  Furthermore, GSK has

 

      committed to freeze the price of Ventolin HFA from

 

      November 5, 2003 until December 31, 2007.

 

                In summary, GSK is committed to and has

 

      global experience in transition to ozone-friendly

 

      formulations.  GSK has currently installed

 

      production capacity to produce 15 million Ventolin

 

      HFA MDIs per year.  We are prepared to expand the

 

      total capacity to approximately 30 million MDIs per

 

      year.

 

                GSK has demonstrated an abiding commitment

 

      to helping patients gain access to our medicines

 

      and, towards this end, has patient-assistance

 

      programs in place to help ensure access to Ventolin

 

      HFA at transition.  Finally, GSK has committed to

 

      provide professional samples and freeze the price

 

                                                               119

 

      of Ventolin HFA.

 

                We expect that the criteria for

 

      transition, as outlined in the 2002 Final Rule,

 

      will be met with the support of all currently

 

      approved albuterol HFA suppliers.  Therefore, GSK

 

      supports a transition date of December 31, 2005

 

      which would allow for a smooth and orderly

 

      transition for patients.

 

                I would like to conclude by, once again,

 

      thanking the advisory committee and the agency for

 

      allowing GlaxoSmithKline the opportunity to present

 

      today.

 

                Thank you.

 

                DR. CHINCHILLI:  Thank you, Dr. Jones.

 

                Let's have our third speaker for this

 

      morning.

 

                DR. GARUTTI:  Members of the committee,

 

      Food and Drug Administration, invited guests,

 

      ladies and gentlemen, good morning.  My name is Dr.

 

      Ron Garutti.  I am a pediatrician and I am Group

 

      Vice President of Global Regulatory Affairs at

 

      Schering-Plough Research Institute.

 

                                                               120

 

                On behalf of Schering-Plough Corporation,

 

      I want to thank the FDA for the opportunity to

 

      address the advisory committee today.

 

                Let me say, at the outset, that our

 

      company firmly supports the principles of the

 

      January 29, 2003 petition of the U.S. Stakeholders,

 

      which you have heard about, which requests an end

 

      to the exemption for albuterol CFC-based in

 

      inhalers.  As pointed out, this exemption, after

 

      all, was never intended to be permanent.

 

                Now, I will not devote any of my

 

      discussion today to the rationale for removing CFCs

 

      from albuterol inhalers as I believe that that

 

      rationale is well understood and accepted by most

 

      interested parties as the right and necessary thing

 

      to do.

 

                In so removing CFCs, the United States

 

      would be accomplishing the transition to a non-CFC

 

      environment that has already successfully been

 

      implemented by most of the European Union, Canada,

 

      Australia, Japan and other countries.

 

                So the important question, then, today,

 

                                                               121

 

      for the committee is not if the transition should

 

      be done but when.  It can be done as soon as FDA,

 

      in conjunction with the healthcare community and

 

      the industry, is prepared to initiate the

 

      transition.

 

                It has been pointed out that in July,

 

      2002, the FDA issued a final rule which set forth

 

      the conditions that would have to be met before an

 

      essential-use designation for albuterol inhalers

 

      could be removed.  Both Drs. Meyer and Sullivan

 

      have noted them.  Schering believes that all of the

 

      necessary elements to remove the essential-use

 

      designation can be met as early as December 31,

 

      2005.

 

                We acknowledge the proposed rule

 

      distributed today and we are pleased to learn that

 

      FDA plans to publish this on June 16.  We are

 

      hopeful that today's discussion will lead to the

 

      establishment of a firm date.

 

                As a company with more than twenty years

 

      of respiratory experience and the first with our

 

      partner 3M to introduce an HFA inhaler to the

 

                                                               122

 

      United States, Schering understands that we, in

 

      conjunction with all of you and other members of

 

      the professional asthma community, will be asking

 

      millions of patients to change their behavior.

 

                We recognize the significance of this

 

      transition to patients and providers alike and we

 

      are sensitive to the fact that ongoing

 

      communication efforts will be essential elements to

 

      ensuring that the transition is smooth and

 

      successful.

 

                To accomplish this effectively, however,

 

      it is critical that FDA establish a clear timeline

 

      to end the exemption because we believe that only

 

      in doing so will there be the necessary stimulus to

 

      drive the kind of provider and patient-behavior

 

      change that will be required.  Schering's

 

      contribution, as well as that of others, to

 

      effecting a successful transition hinges on

 

      implementing the various elements of the transition

 

      at the right time in relation to the effective

 

      date.

 

                In the absence of such a date, it will be

 

                                                               123

 

      difficult to manage these various aspects

 

      efficiently.  For example, patients may not be

 

      receptive to targeted communication efforts until a

 

      fixed date has been established.  It has been

 

      pointed out, in addition, that significant planning

 

      decisions and resource commitments required to

 

      increase current production capacity need to be

 

      made and, for us, we need about eighteen months in

 

      advance of a known effective date.

 

                That being said, Schering is poised to

 

      play a part in a planned orderly transition and we

 

      could be ready for an HFA-only environment as early

 

      as the end of next year.  We believe that for the

 

      FDA to remove the exemption, certain assurances are

 

      required.  These are that safe and effective

 

      alternatives are available, that patients and

 

      providers are knowledgeable about and comfortable

 

      with the use of the inhalers and that industry can

 

      adequately meet the demand.

 

                In the next few minutes, I will point out

 

      that we do have safe and effective alternatives

 

      right now and Schering will have educational

 

                                                               124

 

      programs ready so that patients and providers will

 

      be knowledgeable about and comfortable with their

 

      HFA alternatives and that we can have an adequate

 

      supply and production capacity of Proventil HFA

 

      available again as early as December 31, 2005 or

 

      within eighteen months of an established transition

 

      date.

 

                Now, regarding the safe and effective

 

      alternatives, following the issuance of the

 

      Montreal Protocol in 1987 and after years of

 

      research and development, Schering was the first

 

      company to market, in collaboration with our

 

      partner 3M, a non-CFC inhaler in the United States

 

      in 1997.

 

                Industry researchers had created HFAs that

 

      were more environmentally friendly than CFCs.

 

      These HFAs were then extensively tested to ensure

 

      that they possessed the desired characteristics of

 

      an MDI propellent.  A wide range of toxicology

 

      studies, comparable in scope to that for a new

 

      molecular entity and consisting of acute, chronic

 

      reproductive genetic and carcinogenicity

 

                                                               125

 

      evaluations, established that certain HFA molecules

 

      were, in fact, suitable candidates to replace CFCs

 

      in inhaled delivery systems.

 

                The new technology was then applied to

 

      Proventil and, after a comprehensive clinical

 

      program established that Proventil HFA was both

 

      safe and effective, the FDA approved the product

 

      for marketing clearance in 1996.  In addition to

 

      the clinical studies that were included in the NDA,

 

      3M also conducted a robust observational

 

      postmarketing program which studied more than 6,000

 

      patients.

 

                In the nearly eight years of postmarketing

 

      patient experience to date, more than 17 million

 

      prescriptions for Proventil HFA have been written.

 

      Spontaneously reported adverse events, as you have

 

      heard, have been consistent with the product's

 

      labeling and similar in nature to that of its CFC

 

      counterpart.

 

                Taken together, available data clearly

 

      support the established safety profile of Proventil

 

      HFA and so, yes, we do have safe and effective

 

                                                               126

 

      non-CFC alternatives available right now and, in

 

      fact, with Glaxo's HFA product, there are, as said,

 

      two such products available.

 

                Let's turn now to another assurance

 

      required before removing the exemption, that

 

      relating to education and communication.  Schering

 

      is committed to playing its part in communicating

 

      important information around the transition to both

 

      patients and providers.  Including in that

 

      important information is reiteration of the message

 

      that HFA inhalers are as safe and effective as the

 

      CFC inhalers to which most patients are accustomed.

 

      The HFA inhalers are also similar in size and shape

 

      and as convenient to use.

 

                Now, we all recognize, especially those

 

      who treat asthma patients, that there can be a

 

      significant psychological and emotional component

 

      to asthma and its treatment.  Asthma patients come

 

      to rely on their inhalers and expect a certain type

 

      of experience in using them.  They tend to

 

      associate activity of the drug and subsequent

 

      relief with the forceful sensation of the spray

 

                                                               127

 

      from a CFC inhaler has on the back of the throat.

 

                I would point out that, with an HFA

 

      inhaler, however, there is a softer spray and less

 

      sensation although, of course, the active drug is

 

      still effectively delivered to the lung.  This fact

 

      must this communicated to patients to ensure the

 

      appropriate use of the product.  Patients will also

 

      need to be comfortable with the fact the drug from

 

      an HFA inhaler may taste and smell slightly

 

      different than that from a CFC inhaler.

 

                Schering has always had educational

 

      programs in support of our respiratory-care

 

      business and messages such as those I have just

 

      noted will be included in our developing multipoint

 

      communication and awareness programs intended to

 

      facilitate a safe and orderly transition.

 

                Educational information will be accessible

 

      via many channels including informational websites,

 

      written materials available in physician's offices

 

      and through our professional sales representatives.

 

      Schering has traditionally had strong collaborative

 

      working relationships with relevant national

 

                                                               128

 

      medical associations including both the American

 

      Academy and the American College of Allergy, Asthma

 

      and Immunology, the Academy of Family of

 

      Physicians.  We will continue to work with these

 

      associations and others to develop appropriate

 

      educational materials for patients and providers.

 

                We especially appreciate the efforts of

 

      organizations such as the allergy and asthma

 

      network Mothers of Asthmatics in their own

 

      commitments to educating and supporting the needs

 

      of asthma patients.

 

                Schering is also one of the founding

 

      sponsors of the National Patient Safety Foundation

 

      and has held a seat on its board of directors since

 

      1997.  This group is dedicated to improving patient

 

      safety through educational programs and initiatives

 

      and Schering will continue to provide input and

 

      leadership on issues related to safe medication

 

      use.

 

                As I stated in my introduction, the impact

 

      of an expanded successful patient and provider

 

      education campaign will be highly dependent on

 

                                                               129

 

      implementing the various elements at the right time

 

      in relation to a proposed effective date.  These

 

      programs, to be maximally effective, will need to

 

      be timed in coordination with the transition date

 

      established by FDA so that the asthma community can

 

      be optimally prepared.

 

                On other point related to the transition,

 

      it is, unfortunately, a fact and well known that

 

      many asthma patients do not regularly visit their

 

      healthcare provider.  Schering believes, in

 

      agreement with the U.S. Stakeholders, that the

 

      transition will offer a good opportunity for

 

      physicians and patients to increase their general

 

      dialogue about asthma management.

 

                A visit to the healthcare provider,

 

      prompted by the switch to an HFA inhaler, will

 

      allow for a reassessment of the patient's condition

 

      and adjustment of treatment if deemed appropriate.

 

      It will be especially useful for those patients who

 

      may not have seen a physician for some time.

 

                A third assurance required before removing

 

      the exemption is that an adequate supply and

 

                                                               130

 

      production capacity of the HFA alternative will

 

      exist.  FDA has stated, and you have heard several

 

      times today, that over 50 million albuterol

 

      canisters are sold or distributed in the U.S. each

 

      year.  Schering currently supplies approximately

 

      30 million units annually.

 

                Our manufacturing partner, 3M, stands

 

      ready to expand production in its facilities to

 

      manufacture this amount of Proventil HFA and

 

      Schering and 3M both have confidence that the

 

      necessary capacity can be in place to meet our

 

      share of the expected demand.

 

                While much of the preparatory work to

 

      expand capacity is well underway, advanced planning

 

      activities and significant resource commitments

 

      necessary to formally initiate this process require

 

      some assurance of the timing of the transition.

 

      The overall lead time to execute these steps,

 

      including scale-up to current market demand, is

 

      approximately eighteen months, again, thus, making

 

      a fixed transition date established by FDA critical

 

      for us and our partner.

 

                                                               131

 

                In conclusion, the time to set a

 

      transition date is now.  Schering is confident that

 

      we can meet our share of the demand and ensure that

 

      asthma patients who need Proventil HFA are

 

      adequately served.  The focus throughout the

 

      transition from CFC to HFA inhalers must be on

 

      education and communication efforts towards

 

      patients and providers.  Schering is committed to

 

      playing its part in effecting a successful

 

      transition and supports the removal of the CFC

 

      exemption.

 

                The first step requires that a proposed

 

      final rule be published and a clear date

 

      communicated so that all asthma stakeholders can

 

      act together.  Finally, Schering believes the U.S.

 

      can join the group of countries who have already

 

      undergone a successful removal of the exemption

 

      because we do have safe and effective FDA

 

      alternatives now.  We will be educating patients

 

      and providers and ensure their comfort level with

 

      the transition and industry can adequately meet the

 

      supply and demand.

 

                                                               132

 

                Thank you.

 

                DR. CHINCHILLI:  Thank you, Dr. Garutti.

 

      Do the committee members have any questions of our

 

      three open presenters this morning?  Dr. Schatz?

 

                DR. SCHATZ:  I guess a question for the

 

      stakeholders.  The presentation talked, actually,

 

      about two aspects of concern.  One was CFC

 

      availability, itself, and then, obviously, the

 

      detrimental aspects.  But I was trying to get some

 

      sense as to what the relative concerns were and if,

 

      in fact, if CFC availability were assured, would

 

      that change the thinking in terms of a time line?

 

                MS. WEXLER:  If CFC availability was--

 

                DR. SCHATZ:  A fair amount has been

 

      emphasized about the concern as to whether CFCs

 

      will continue to be available in terms of the

 

      production as a rationale for the December 2005

 

      date.  My question was to what extent that one

 

      factor is important and if CFC availability were

 

      assured, if the production were not an issue, would

 

      that affect your thinking in terms of a transition

 

      date?

 

                                                               133

 

                MS. WEXLER:  No.  I think that they work

 

      together to signal that these chemicals are being

 

      eliminated.  There is a reason that Honeywell has

 

      been asked to shut the manufacturing plant in the

 

      Netherlands and that is because the Dutch

 

      government does not want CFCs produced on its soil.

 

      It is a political statement about getting out of

 

      these chemicals.

 

                To answer your question specifically, if

 

      Baton Rouge were able to produce, it is not clear

 

      that the international community would continue to

 

      authorize those quantities and that would put the

 

      stakeholders in the position of suggesting that we

 

      don't care about international commitments.

 

                The U.S., the government, has made a

 

      commitment to comply with the Montreal Protocol and

 

      so producing in Baton Rouge is only part of the

 

      equation.  It is that gets us the potential to use

 

      them.  But the right to use them legally needs to

 

      be granted by the parties to the protocol.  So they

 

      have to work together in order for us to be able to

 

      go forward.

 

                                                               134

 

                I think what, in some ways, you are asking

 

      is would we support renouncing the protocol?

 

                DR. SCHATZ:  No.  It is a matter of would

 

      the date, would your date, change.  I was trying to

 

      get the sensitivity of your position to CFC

 

      availability versus other considerations relative

 

      to the date you suggest.

 

                MS. WEXLER:  Again, I think that they work

 

      together.  Given what we know about the timeline,

 

      the U.S.--forgive me; I want to make sure it is

 

      clear.  We ask to use CFCs, wherever we get them

 

      from.  Regardless of where they are produced, each

 

      country must ask the international process sort of

 

      at the beginning of the year.  We just put in our

 

      request and those requests are two years in

 

      advance.

 

                So the request that the U.S. recently

 

      submitted was for 2006 quantities.  That request

 

      was not welcomed completely.  It was suggested that

 

      the U.S. might want to reconsider that nomination

 

      in light of this rulemaking or the rule that is go

 

      forward.

 

                                                               135

 

                So even if supply weren't necessarily an

 

      issue, I think that it would be foolish for us to

 

      believe that the international community is going

 

      to continue to provide authorization to use those

 

      CFCs indefinitely.  So we are talking about a

 

      2005-2006 timeframe for getting out of this and not

 

      worrying about either of those conditions, of CFC

 

      supply or the international community not granting

 

      authorizations.

 

                I think that, as we have heard, the

 

      process of transitioning, making sure that the

 

      HFA-installed capacity is there, making sure we

 

      don't do anything precipitous and have a problem

 

      and then have no CFC production capability and the

 

      stockpiles of the CFCs that are available sort of

 

      suggest that we want to kind of look towards the

 

      sooner rather than later so that we buy ourselves

 

      some time.

 

                In other words, I don't think the protocol

 

      parties will look kindly at a nomination for 2007

 

      or 2008 regardless of whether Baton Rouge actually

 

      ends up coming on line in a legal way.

 

                                                               136

 

                DR. CHINCHILLI:  Thank you.   Dr.

 

      Atkinson?

 

                DR. ATKINSON:  I sort of get the

 

      impression that one of the big concerns among the

 

      committee members and the FDA also is the

 

      possibility that a small percentage of asthma

 

      patients might be unable to purchase the HFA units

 

      that they need.  GSK has a program, or described a

 

      program, that was going to assist with that.  I

 

      wanted to ask Dr. Garutti if Schering had any such

 

      program and if they were considering creating one

 

      if they don't have one now.

 

                DR. GARUTTI:  Let me say this is a patient

 

      group and a provider group that we care very deeply

 

      about.  We are committed to the respiratory

 

      business.  We have been in it a long time and we

 

      are going to do whatever is necessary to serve our

 

      patient population.

 

                First and foremost there is to make sure

 

      that there is Proventil HFA available when we do

 

      transition to the HFA-only environment.  Currently,

 

      as I have pointed out, that will entail a

 

                                                               137

 

      significant ramp-up and a significant expenditure

 

      of cost to get there.  And we are confident we will

 

      get there.

 

                In fact, Schering-Plough does have a

 

      patient assistance program.  It is called SP Cares.

 

      We have had it since, I believe, the mid-1990s.  It

 

      has similar eligibility requirements to those of

 

      Glaxo's program, not entirely the same but similar.

 

      Last year along we provided free drug of our

 

      primary-care products including Proventil HFA to

 

      some 75,000 low-income uninsured patients.

 

                Periodically, we review the elements of

 

      this program and criteria and we are committed to

 

      continuing this program.

 

                DR. CHINCHILLI:  Thank you.  Dr. Moss; you

 

      had a question?

 

                DR. MOSS:  I was going to ask something

 

      along the same lines.  Maybe the people from GSK

 

      and Schering can talk about how they are going to

 

      market those programs for the uninsured, if they

 

      have any plans for how to make physicians aware of

 

      these programs.

 

                                                               138

 

                MS. WEXLER:  I wanted to point out that,

 

      in anticipation of this move, the stakeholders, on

 

      our website which is at inhalertransition.org, has

 

      listed all of the patient-assistance programs and

 

      has link to them so that our member organizations

 

      can now start to disseminate that information.  So

 

      we also will work with the companies to promote

 

      these.

 

                DR. JONES:  Yes.  Bridges to Access,

 

      actually, at the moment, has 435,000 patients in

 

      its program.  We have done a lot and will endeavor

 

      to meet and strive towards this end.  We have put a

 

      lot of programs in place in order to be able to

 

      reach as many people as possible and we will

 

      continue to have these outreach efforts in place to

 

      allow physicians and their associates to actually

 

      be aware of these programs.

 

                But, as I say, we have 435,000 at the

 

      moment in the Bridges to Access program.

 

                DR. CHINCHILLI:  Thank you.   Dr. Garutti?

 

                DR. GARUTTI:  I am not sure there is much

 

      more we can add.  As we have indicated, we are

 

                                                               139

 

      developing many aspects of our communication

 

      program.  This is one element of them, the

 

      awareness of the SP Cares program and we are going

 

      to be working with various organizations that we

 

      mentioned to make sure that it is more widely

 

      communicated now as we transfer to an HFA-only

 

      environment.

 

                DR. CHINCHILLI:  Any other questions from

 

      committee members?  If not, we are going to break

 

      for lunch.  I'm sorry; Dr. Meyer.  I didn't see

 

      you.

 

                DR. MEYER:  Sorry; not to delay lunch.  I

 

      did want to make a clarification on an issue that

 

      was left open from Ms. Wexler's talk earlier about

 

      how the CFC sources is handled by the FDA because I

 

      think she left that as kind of an open question.

 

                Without getting into the details of the

 

      Baton Rouge situation, what I would say is that the

 

      FDA does not approve a CFC source, per se.  What we

 

      have done is we set standards for the purity that

 

      is acceptable for CFCs when used in metered-dose

 

      inhalers.  It is the expectation that the sponsor

 

                                                               140

 

      of a product that uses those CFCs will provide us

 

      evidence, both from the manufacturer as well as

 

      their own testing, that the CFCs meet those

 

      specifications and, if they do, then, in fact, they

 

      can be used in that product.

 

                DR. CHINCHILLI:  Thank you for the

 

      clarification.  Let me make sure nobody else has

 

      anything.  Okay.  We will break for lunch.  We plan